ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.356G>C (p.Arg119Pro)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_170707.4(LMNA):c.356G>C (p.Arg119Pro)
Variation ID: 48064 Accession: VCV000048064.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 156115274 (GRCh38) [ NCBI UCSC ] 1: 156085065 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 19, 2017 Feb 14, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_170707.4:c.356G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Arg119Pro missense NM_005572.4:c.356G>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005563.1:p.Arg119Pro missense NM_001282625.2:c.356G>C NP_001269554.1:p.Arg119Pro missense NM_001282626.2:c.356G>C NP_001269555.1:p.Arg119Pro missense NM_001406983.1:c.356G>C NP_001393912.1:p.Arg119Pro missense NM_001406984.1:c.356G>C NP_001393913.1:p.Arg119Pro missense NM_001406985.1:c.356G>C NP_001393914.1:p.Arg119Pro missense NM_001406986.1:c.-68G>C 5 prime UTR NM_001406990.1:c.-46G>C 5 prime UTR NM_001406991.1:c.356G>C NP_001393920.1:p.Arg119Pro missense NM_001406992.1:c.356G>C NP_001393921.1:p.Arg119Pro missense NM_001406993.1:c.-203+8451G>C intron variant NM_001406994.1:c.-309G>C 5 prime UTR NM_001406995.1:c.-46G>C 5 prime UTR NM_001406999.1:c.-489G>C 5 prime UTR NM_001407000.1:c.-309G>C 5 prime UTR NM_001407001.1:c.-152G>C 5 prime UTR NM_001407002.1:c.-46G>C 5 prime UTR NM_001407003.1:c.-203+8451G>C intron variant NM_170708.4:c.356G>C NP_733822.1:p.Arg119Pro missense NR_047544.1:n.997G>C NC_000001.11:g.156115274G>C NC_000001.10:g.156085065G>C NG_008692.2:g.37702G>C LRG_254:g.37702G>C LRG_254t1:c.356G>C LRG_254p1:p.Arg119Pro LRG_254t2:c.356G>C LRG_254p2:p.Arg119Pro LRG_254t3:c.356G>C LRG_254p3:p.Arg119Pro - Protein change
- R119P
- Other names
- p.R119P:CGC>CCC
- Canonical SPDI
- NC_000001.11:156115273:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LMNA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1810 | 2087 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Sep 6, 2016 | RCV000041347.17 | |
Uncertain significance (2) |
criteria provided, single submitter
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Feb 25, 2020 | RCV000767136.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 21, 2024 | RCV003581568.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Sep 06, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics Inc
Accession: SCV000614028.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Uncertain significance
(Feb 25, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000234735.14
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Reported in association with dilated cardiomyopathy; however, additional clinical information was not provided (Pugh et al., 2014; Walsh et al., 2017); Reported in ClinVar by … (more)
Reported in association with dilated cardiomyopathy; however, additional clinical information was not provided (Pugh et al., 2014; Walsh et al., 2017); Reported in ClinVar by other clinical laboratories as a variant of uncertain significance (ClinVar Variant ID# 48064; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24503780, 27532257, 28679633) (less)
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Uncertain significance
(Aug 20, 2014)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000065040.5
First in ClinVar: May 03, 2013 Last updated: Dec 19, 2017 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 1
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Uncertain significance
(Jan 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004292904.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 119 of the LMNA protein (p.Arg119Pro). … (more)
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 119 of the LMNA protein (p.Arg119Pro). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with arrhythmogenic cardiomyopathy and/or dilated cardiomyopathy (PMID: 24503780, 27532257, 36548481). ClinVar contains an entry for this variant (Variation ID: 48064). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with inconclusive levels of altered splicing (PMID: 28679633). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely pathogenic
(Dec 15, 2017)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000925143.1
First in ClinVar: Jul 01, 2019 Last updated: Jul 01, 2019 |
Comment:
We identified this variant in a patient with dilated cardiomyopathy and limb girdle muscular dystrophy. SCICD Classification: likely pathogenic variant based on absence in the … (more)
We identified this variant in a patient with dilated cardiomyopathy and limb girdle muscular dystrophy. SCICD Classification: likely pathogenic variant based on absence in the general population, moderate case data, moderate segregation and position of variant. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"), however family members should be counseled about probabilistic nature of genetic testing. Additional case data or segregation could provide additional evidence towards pathogenicity. Gene-level evidence: LMNA: Pathogenic variants in LMNA cause clinically variable diseases, called the laminopathies. These include dilated cardiomyopathy (DCM), which is typically accompanied by conduction system disease and/or arrhythmias. Sudden cardiac death can occur before the onset of LV dilation, warranting early consideration of an ICD. Other laminopathies include Emery-Dreifuss muscular dystrophy, Hutchinson-Gilford progeria syndrome and lipodystrophies, among others. Region-level evidence: according to Amr et al 2016, this variant falls within the filament domain, a region that is greatly enriched for intolerance to variant in cases vs. controls (OR: 152). Case data (not including our patient): 3 · I contacted Gene Dx and they reported they have seen the variant in 2 probands (one who harbored additional variants) who had cardiomyopathy panels. LMM has seen it in 1 patient and it overlaps with that reported by Pugh 2014. · Cases in the literature: 1 (redudant with lab data_ ? Pugh 2014: reported in 44yo woman with clinical dx of DCM with VF and family history of arrhythmia and sudden death. Classified as likely pathogenic. No other disease causing variants reported. Segregation data: To our knowledge, clnical colleagues at a different institution have seen this variant in a family where it segregates in 4 affected family members (may overlap with cases reported by genetic testing laboratories. Our patient's affected brother was apparently tested and was positive. Functional data: None reported In silico data (missense variants only): Per various prediction models in varsome.com, the variant is disease causing/deleterious. Of note, the variant does alter the last amino acid at the exon/intron junction, which could possible affect splicing. Nearby pathogenic variants at this codon or neighboring codons: A different variant at the same position (c.354_355delGCinsAG; p.Arg119Gly) is listed as likely pathogenic in ClinVar by Blueprint. No summary evidence provided. Population data: Absent The variant is absent from the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Per Varsome.org, the average coverage at that site in genomes is 33x whereas in exomes it is 60x. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Intrinsic Atrial Myopathy Precedes Left Ventricular Dysfunction and Predicts Atrial Fibrillation in Lamin A/C Cardiomyopathy. | Tremblay-Gravel M | Circulation. Genomic and precision medicine | 2023 | PMID: 36548481 |
Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing. | Ito K | Proceedings of the National Academy of Sciences of the United States of America | 2017 | PMID: 28679633 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. | Pugh TJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24503780 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs397517902 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.