ClinVar Genomic variation as it relates to human health
NM_006306.4(SMC1A):c.1487G>A (p.Arg496His)
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_006306.4(SMC1A):c.1487G>A (p.Arg496His)
Variation ID: 11675 Accession: VCV000011675.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.22 X: 53409120 (GRCh38) [ NCBI UCSC ] X: 53436051 (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 Sep 19, 2018 Feb 14, 2024 Apr 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006306.4:c.1487G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006297.2:p.Arg496His missense NM_001281463.1:c.1421G>A NP_001268392.1:p.Arg474His missense NC_000023.11:g.53409120C>T NC_000023.10:g.53436051C>T NG_006988.2:g.18551G>A LRG_773:g.18551G>A LRG_773t1:c.1421G>A LRG_773p1:p.Arg474His LRG_773t2:c.1487G>A LRG_773p2:p.Arg496His Q14683:p.Arg496His - Protein change
- R496H, R474H
- Other names
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- Canonical SPDI
- NC_000023.11:53409119:C:T
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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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SMC1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
900 | 1064 |
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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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Apr 9, 2023 | RCV000012441.23 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 5, 2021 | RCV001577833.3 |
Submissions - Germline
Classification
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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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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Congenital muscular hypertrophy-cerebral syndrome
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058839.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The variant has been previously reported as de novo in a similarly affected individual (PMID: 22140011, PS2_S). Same nucleotide change resulting in same amino acid … (more)
The variant has been previously reported as de novo in a similarly affected individual (PMID: 22140011, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011675, PMID:17273969, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000841238, PMID:17273969, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95, 3CNET: 0.977, PP3_P). A missense variant is a common mechanism associated with Cornelia de Lange syndrome 2 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Clinodactyly of the 5th finger (present) , Deeply set eye (present) , Small hand (present) , Drooling (present) , Abnormal facial shape (present) , Global … (more)
Clinodactyly of the 5th finger (present) , Deeply set eye (present) , Small hand (present) , Drooling (present) , Abnormal facial shape (present) , Global developmental delay (present) , Intellectual disability (present) , Microcephaly (present) , Overlapping toe (present) , Thick eyebrow (present) , Seizure (present) , Brachymetatarsus 4 (present) , Synophrys (present) , Thin upper lip vermilion (present) (less)
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Pathogenic
(Mar 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cornelia de Lange syndrome 2
Affected status: yes
Allele origin:
de novo
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Baylor Genetics
Accession: SCV000747077.1
First in ClinVar: Sep 19, 2018 Last updated: Sep 19, 2018 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Feb 05, 2021)
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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: SCV001805299.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); … (more)
Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28835994, 28548707, 30158690, 24461912, 22581668, 17273969, 19262687, 20583156, 26725122, 19701948, 18996922, 22140011) (less)
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Pathogenic
(Apr 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital muscular hypertrophy-cerebral syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001592682.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg496 amino acid residue in SMC1A. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg496 amino acid residue in SMC1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17273969; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SMC1A function (PMID: 18996922). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMC1A protein function. ClinVar contains an entry for this variant (Variation ID: 11675). This missense change has been observed in individual(s) with Cornelia de Lange syndrome (PMID: 17273969, 22140011, 24461912). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 496 of the SMC1A protein (p.Arg496His). (less)
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Pathogenic
(Mar 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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Congenital muscular hypertrophy-cerebral syndrome
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368008.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP2,PP3.
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Pathogenic
(Feb 01, 2009)
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no assertion criteria provided
Method: literature only
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CORNELIA DE LANGE SYNDROME 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000032675.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 22, 2019 |
Comment on evidence:
In 2 sisters with a variant form of Cornelia de Lange syndrome (CDLS2; 300590), Deardorff et al. (2007) identified a 1487G-A transition in the SMC1A … (more)
In 2 sisters with a variant form of Cornelia de Lange syndrome (CDLS2; 300590), Deardorff et al. (2007) identified a 1487G-A transition in the SMC1A gene that resulted in an arg496-to-his substitution (R496H). Both had psychomotor delay and moderately severe mental retardation. One had pulmonic stenosis. Both had gastroesophageal reflux. Revenkova et al. (2009) showed that R496H-mutant SMC1A affected the affinity of SMC hinge dimers for DNA. Mutated hinge dimers bound DNA with higher affinity than wildtype proteins. SMC1A-mutated Cornelia de Lange syndrome cell lines displayed genomic instability and sensitivity to ionizing radiation and interstrand crosslinking agents. (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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Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies. | Yuan B | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30158690 |
Epileptic features in Cornelia de Lange syndrome: case report and literature review. | Pavlidis E | Brain & development | 2014 | PMID: 24461912 |
SMC1A codon 496 mutations affect the cellular response to genotoxic treatments. | Mannini L | American journal of medical genetics. Part A | 2012 | PMID: 22140011 |
Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA. | Revenkova E | Human molecular genetics | 2009 | PMID: 18996922 |
Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation. | Deardorff MA | American journal of human genetics | 2007 | PMID: 17273969 |
Text-mined citations for rs122454123 ...
HelpRecord last updated Feb 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.