NM_170707.4(LMNA):c.1184C>T (p.Ser395Leu) AND Primary dilated cardiomyopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 3, 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:: RCV003996499.2

Allele description [Variation Report for NM_170707.4(LMNA):c.1184C>T (p.Ser395Leu)]

NM_170707.4(LMNA):c.1184C>T (p.Ser395Leu)

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.1184C>T (p.Ser395Leu)

HGVS:

NC_000001.11:g.156136240C>T
NG_008692.2:g.58668C>T
NM_001257374.3:c.848C>T
NM_001282624.2:c.941C>T
NM_001282625.2:c.1184C>T
NM_001282626.2:c.1184C>T
NM_005572.4:c.1184C>T
NM_170707.4:c.1184C>TMANE SELECT
NM_170708.4:c.1184C>T
NP_001244303.1:p.Ser283Leu
NP_001269553.1:p.Ser314Leu
NP_001269554.1:p.Ser395Leu
NP_001269555.1:p.Ser395Leu
NP_005563.1:p.Ser395Leu
NP_733821.1:p.Ser395Leu
NP_733822.1:p.Ser395Leu
LRG_254t2:c.1184C>T
LRG_254:g.58668C>T
NC_000001.10:g.156106031C>T
NM_170707.2:c.1184C>T
NM_170707.3:c.1184C>T

Protein change:

S283L

Links:

dbSNP: rs267607561

NCBI 1000 Genomes Browser:

rs267607561

Molecular consequence:

NM_001257374.3:c.848C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.941C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1184C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1184C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1184C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1184C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1184C>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
SCV004816147	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Apr 3, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17711925, 24623722, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004816147

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Apr 3, 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	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

New metabolic phenotypes in laminopathies: LMNA mutations in patients with severe metabolic syndrome.

Decaudain A, Vantyghem MC, Guerci B, Hécart AC, Auclair M, Reznik Y, Narbonne H, Ducluzeau PH, Donadille B, Lebbé C, Béréziat V, Capeau J, Lascols O, Vigouroux C.

J Clin Endocrinol Metab. 2007 Dec;92(12):4835-44. Epub 2007 Aug 21.

PubMed [citation]

PMID:: 17711925

Systematic identification of pathological lamin A interactors.

Dittmer TA, Sahni N, Kubben N, Hill DE, Vidal M, Burgess RC, Roukos V, Misteli T.

Mol Biol Cell. 2014 May;25(9):1493-510. doi: 10.1091/mbc.E14-02-0733. Epub 2014 Mar 12.

PubMed [citation]

PMID:: 24623722
PMCID:: PMC4004598

See all PubMed Citations (3)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004816147.1

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

Description

This missense variant replaces serine with leucine at codon 395 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). In vitro functional studies suggest that this variant may not have significant impact on LMNA protein binding activity (PMID: 24623722). This variant has been reported in an individual affected with a peripheral neuropathy phenotype (PMID: 17711925). This variant has been identified in 4/279930 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		1	not provided	not provided	not provided

Last Updated: Jul 29, 2024

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