NM_170707.4(LMNA):c.1027C>T (p.Arg343Trp) AND Dilated cardiomyopathy 1A

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Feb 15, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001096835.8

Allele description [Variation Report for NM_170707.4(LMNA):c.1027C>T (p.Arg343Trp)]

NM_170707.4(LMNA):c.1027C>T (p.Arg343Trp)

Gene:

LMNA:lamin A/C [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q22

Genomic location:

Preferred name:

NM_170707.4(LMNA):c.1027C>T (p.Arg343Trp)

HGVS:

NC_000001.11:g.156135991C>T
NG_008692.2:g.58419C>T
NM_001257374.3:c.691C>T
NM_001282624.2:c.784C>T
NM_001282625.2:c.1027C>T
NM_001282626.2:c.1027C>T
NM_005572.4:c.1027C>T
NM_170707.4:c.1027C>TMANE SELECT
NM_170708.4:c.1027C>T
NP_001244303.1:p.Arg231Trp
NP_001269553.1:p.Arg262Trp
NP_001269554.1:p.Arg343Trp
NP_001269555.1:p.Arg343Trp
NP_005563.1:p.Arg343Trp
NP_005563.1:p.Arg343Trp
NP_733821.1:p.Arg343Trp
NP_733822.1:p.Arg343Trp
LRG_254t1:c.1027C>T
LRG_254t2:c.1027C>T
LRG_254:g.58419C>T
LRG_254p1:p.Arg343Trp
NC_000001.10:g.156105782C>T
NM_005572.3:c.1027C>T
NM_170707.2:c.1027C>T
NM_170707.3:c.1027C>T

Protein change:

R231W

Links:

dbSNP: rs749784223

NCBI 1000 Genomes Browser:

rs749784223

Molecular consequence:

NM_001257374.3:c.691C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.784C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1027C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1027C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1027C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1027C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1027C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Dilated cardiomyopathy 1A (CMD1A)
Synonyms:: CARDIOMYOPATHY, CONGESTIVE; CARDIOMYOPATHY, DILATED, WITH CONDUCTION DEFECT 1; Idiopathic dilated cardiomyopathy; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007269; MedGen: C1449563; Orphanet: 300751; OMIM: 115200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001253079	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV003928186	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	criteria provided, single submitter (K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)	Likely risk allele (Feb 15, 2024)	unknown	research	PubMed (3) [See all records that cite these PMIDs] 23702046, 12628721, 17334235 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001253079

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 13, 2018)

germline

clinical testing

Citation Link,

SCV003928186

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

criteria provided, single submitter

(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)

Likely risk allele
(Feb 15, 2024)

unknown

research

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

LMNA mutations in Polish patients with dilated cardiomyopathy: prevalence, clinical characteristics, and in vitro studies.

Saj M, Bilinska ZT, Tarnowska A, Sioma A, Bolongo P, Sobieszczanska-Malek M, Michalak E, Golen D, Mazurkiewicz L, Malek L, Walczak E, Fidzianska A, Grzybowski J, Przybylski A, Zielinski T, Korewicki J, Tesson F, Ploski R.

BMC Med Genet. 2013 May 23;14:55. doi: 10.1186/1471-2350-14-55.

PubMed [citation]

PMID:: 23702046
PMCID:: PMC3666888

Natural history of dilated cardiomyopathy due to lamin A/C gene mutations.

Taylor MR, Fain PR, Sinagra G, Robinson ML, Robertson AD, Carniel E, Di Lenarda A, Bohlmeyer TJ, Ferguson DA, Brodsky GL, Boucek MM, Lascor J, Moss AC, Li WL, Stetler GL, Muntoni F, Bristow MR, Mestroni L; Familial Dilated Cardiomyopathy Registry Research Group..

J Am Coll Cardiol. 2003 Mar 5;41(5):771-80. Erratum in: J Am Coll Cardiol. 2003 Aug 6;42(3):590.

PubMed [citation]

PMID:: 12628721

See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001253079.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic, SCV003928186.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	research	PubMed (3)

Description

Potent mutations in LMNA gene can lead to structural alteration in skeletal and cardiac muscle by altering the structure of Lamin A and Lamin C. It is associated with dilated cardiomyopathy and skeletal muscle dystrophies. However no sufficient evidence is found to ascertain the role of this particular variant rs749784223, yet.This variant is a potent moderate impact, deleterious variant with a CADD score of 25.8. This gene is found to be frequently associated with Dilated cardiomyopathy cases as per recent evidence as well with sufficient scientific evidence to support the reported classification.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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