NM_170707.4(LMNA):c.991C>T (p.Arg331Trp) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 10, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003227732.2

Allele description [Variation Report for NM_170707.4(LMNA):c.991C>T (p.Arg331Trp)]

NM_170707.4(LMNA):c.991C>T (p.Arg331Trp)

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.991C>T (p.Arg331Trp)

HGVS:

NC_000001.11:g.156135955C>T
NG_008692.2:g.58383C>T
NM_001257374.3:c.655C>T
NM_001282624.2:c.748C>T
NM_001282625.2:c.991C>T
NM_001282626.2:c.991C>T
NM_005572.4:c.991C>T
NM_170707.4:c.991C>TMANE SELECT
NM_170708.4:c.991C>T
NP_001244303.1:p.Arg219Trp
NP_001269553.1:p.Arg250Trp
NP_001269554.1:p.Arg331Trp
NP_001269555.1:p.Arg331Trp
NP_005563.1:p.Arg331Trp
NP_733821.1:p.Arg331Trp
NP_733822.1:p.Arg331Trp
LRG_254t2:c.991C>T
LRG_254:g.58383C>T
NC_000001.10:g.156105746C>T
NM_170707.2:c.991C>T

Protein change:

R219W

Links:

dbSNP: rs879253898

NCBI 1000 Genomes Browser:

rs879253898

Molecular consequence:

NM_001257374.3:c.655C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.748C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.991C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.991C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.991C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.991C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.991C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

Name:: Restrictive dermopathy 2 (RSDM2)
Synonyms:: RESTRICTIVE DERMOPATHY 2, LETHAL
Identifiers:: MONDO: MONDO:0030781; MedGen: C5676942; OMIM: 619793

Recent activity

Clear Turn Off Turn On

intracellular protein transporter [Arabidopsis thaliana]
intracellular protein transporter [Arabidopsis thaliana]
gi|30687652|ref|NP_194491.2|

Protein
Gm29064 AND (alive[prop]) (0)
Gene

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003925261	New York Genome Center	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Uncertain significance (Aug 10, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003925261

New York Genome Center

criteria provided, single submitter

(NYGC Assertion Criteria 2020)

Uncertain significance
(Aug 10, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Details of each submission

From New York Genome Center, SCV003925261.1

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

Description

The c.991C>T, p.(Arg331Trp) variant identified in the LMNA gene substitutes a well conserved Arginine for Tryptophan at amino acid 331/665 (exon 6/12) in the coiled-coil 2B domain of the encoded protein [PMID: 17377071]. The c.991C>T variant is observed in 4 alleles (0.00078% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. In silico algorithms predict this variant to be Damaging to the function of the canonical transcript (REVEL; score=0.842). This variant has been reported as both Likely Pathogenic (n=1) and as a Variant of Uncertain Significance (n=2) in ClinVar (VarID:245682), and has been reported in one individual with a presumed Laminopathy but without specific clinical details [PMID:31476771] and three individuals without documented cardiac phenotypes [PMID:31383942, Supp Table S4A]. However, a different amino acid change at the same amino acid (p.(Arg331Gln); VarID:48098) has been reported as Pathogenic in ClinVar and is reported in affected individuals in the literature [PMID:28790152]. A second independent amino acid change at the p.Arg331 position (p.(Arg331Leu)) has been reported in compound heterozygous state in a female proband with severe left ventricular systolic dysfunction, supraventricular and ventricular arrhythmias [PMID: 34768595] though it is not clear if the variant identified in trans with the p.Arg331Leu variant (p.Arg216His) is causative of the phenotype, the p.Arg331Leu variant alone is causative, or both variants contribute to the phenotype. Based on available evidence this c.991C>T p.(Arg331Trp) variant identified in LMNA is classified as a Variant of Uncertain Significance.

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

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine