NM_170707.4(LMNA):c.1381G>T (p.Asp461Tyr) AND Primary dilated cardiomyopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 18, 2023
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:: RCV003996504.2

Allele description [Variation Report for NM_170707.4(LMNA):c.1381G>T (p.Asp461Tyr)]

NM_170707.4(LMNA):c.1381G>T (p.Asp461Tyr)

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.1381G>T (p.Asp461Tyr)

HGVS:

NC_000001.11:g.156136921G>T
NG_008692.2:g.59349G>T
NM_001257374.3:c.1045G>T
NM_001282624.2:c.1138G>T
NM_001282625.2:c.1381G>T
NM_001282626.2:c.1381G>T
NM_005572.4:c.1381G>T
NM_170707.4:c.1381G>TMANE SELECT
NM_170708.4:c.1381G>T
NP_001244303.1:p.Asp349Tyr
NP_001269553.1:p.Asp380Tyr
NP_001269554.1:p.Asp461Tyr
NP_001269555.1:p.Asp461Tyr
NP_005563.1:p.Asp461Tyr
NP_733821.1:p.Asp461Tyr
NP_733822.1:p.Asp461Tyr
LRG_254t1:c.1381G>T
LRG_254t2:c.1381G>T
LRG_254:g.59349G>T
NC_000001.10:g.156106712G>T
NM_005572.3:c.1381G>T
NM_170707.2:c.1381G>T
NM_170707.3:c.1381G>T
P02545:p.Asp461Tyr

Protein change:

D349Y

Links:

UniProtKB: P02545#VAR_064973; dbSNP: rs267607642

NCBI 1000 Genomes Browser:

rs267607642

Molecular consequence:

NM_001257374.3:c.1045G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.1138G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1381G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1381G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1381G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1381G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1381G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Primary dilated cardiomyopathy (DCM)
Synonyms:: Dilated Cardiomyopathy
Identifiers:: EFO: EFO_0000407; MONDO: MONDO:0005021; MeSH: D002311; MedGen: C0007193; Human Phenotype Ontology: HP:0001644

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004815066	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 18, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20848652, 28679633, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004815066

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 18, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations.

Scharner J, Brown CA, Bower M, Iannaccone ST, Khatri IA, Escolar D, Gordon E, Felice K, Crowe CA, Grosmann C, Meriggioli MN, Asamoah A, Gordon O, Gnocchi VF, Ellis JA, Mendell JR, Zammit PS.

Hum Mutat. 2011 Feb;32(2):152-67. doi: 10.1002/humu.21361. Epub 2011 Jan 25.

PubMed [citation]

PMID:: 20848652

Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing.

Ito K, Patel PN, Gorham JM, McDonough B, DePalma SR, Adler EE, Lam L, MacRae CA, Mohiuddin SM, Fatkin D, Seidman CE, Seidman JG.

Proc Natl Acad Sci U S A. 2017 Jul 18;114(29):7689-7694. doi: 10.1073/pnas.1707741114. Epub 2017 Jul 5.

PubMed [citation]

PMID:: 28679633
PMCID:: PMC5528995

See all PubMed Citations (3)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004815066.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces aspartic acid with tyrosine at codon 461 of the lamin A/C protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools and conservation analyses are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with cardiomyopathy (PMID: 28679633) and two related individuals affected with dilated cardiomyopathy (Nicolette et al.). This variant has been reported in compound heterozygosity with c.1381-1G>T in an individual affected with a severe form of Emery-Dreifuss muscular dystrophy (PMID: 20848652). This variant has been identified in 2/250058 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant 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	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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