Submissions for variant NM_170707.4(LMNA):c.1318G>A (p.Val440Met)

gnomAD frequency: 0.00002  dbSNP: rs121912493

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000552191	SCV000657800	pathogenic	Charcot-Marie-Tooth disease type 2	2023-06-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LMNA function (PMID: 17848409). 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 LMNA protein function. ClinVar contains an entry for this variant (Variation ID: 14520). This missense change has been observed in individual(s) with autosomal recessive mandibuloacral dysplasia and/or the severe form of autosomal recessive familial partial lipodystrophy (FPLD) (PMID: 10999845, 17848409). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant dilated cardiomyopathy and/or autosomal dominant Hutchinson–Gilford progeria syndrome (PMID: 19875404, 25371241, 30871747); however, the role of the variant in this condition is currently unclear. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 440 of the LMNA protein (p.Val440Met).
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001172618	SCV001335681	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001186220	SCV001352586	uncertain significance	Cardiomyopathy	2022-07-21	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 440 of the LMNA protein and is located in the lamin tail domain that is involved in binding to DNA and other proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that cells carrying this variant in the compound heterozygous state display altered nuclear morphology and heterochromatin organization (PMID: 17848409) and that this variant may affect interaction with other proteins (PMID: 24623722). However, the clinical relevance of these observations is not known. This variant has also been reported in heterozygosity in 2 individuals with dilated cardiomyopathy (PMID: 19875404, 30871747) and in an individual affected with Hutchinson-Gilford progeria syndrome (PMID: 25371241). This variant has been reported in compound heterozygosity in an individual affected with Dunnigan-type partial lipodystrophy (PMID: 10999845) and in an individual affected with mandibuloacral dysplasia type A-like phenotype (PMID: 17848409). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264435	SCV001442586	uncertain significance	not specified	2020-10-27	criteria provided, single submitter	clinical testing	Variant summary: LMNA c.1318G>A (p.Val440Met) results in a conservative amino acid change located in the Lamin tail domain (IPR001322) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248838 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1318G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy (e.g. Moller_2009, Sousa_2019, Martins_2019), but also unaffected family members (e.g. Moller_2009). The variant has also been reported in a compound heterozygous state with a pathogenic variant in an individual diagnosed with Mandibuloacral dysplasia type A (MADA), consistent with an autosomal recessive pattern of inhertiance for this disease (e.g. Lombardi_2007). Other reports in the literature include the variant in a compound heterozygous state with another pathogenic variant in LMNA in an individual with a severe form of Dunnigan-type partial lipodystrophy (FPLD, Hegele_2000), leading the authors to suggest that the variant may modify this phenotype, and in an individual with Hutchinson-Gilford Progeria Syndrome (HGPD, Zhang_2016). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Several publications report experimental evidence evaluating an impact on protein function, however, do not allow convincing conclusions about the variant effect (e.g. Nitta_2006, Lombardi_2007, Dittmer_2014). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as uncertain significance. Based on the evidence outlined above, until additional information becomes available, the variant was classified as uncertain significance.
Ambry Genetics	RCV002381252	SCV002694766	uncertain significance	Cardiovascular phenotype	2023-04-17	criteria provided, single submitter	clinical testing	The p.V440M variant (also known as c.1318G>A), located in coding exon 7 of the LMNA gene, results from a G to A substitution at nucleotide position 1318. The valine at codon 440 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in the compound heterozygous state (in trans) with the p.R482Q mutation in a proband with a severe form of familial partial lipodystrophy; however, the proband's mother who had only the p.V440M allele was reportedly unaffected (Hegele RA et al. J Clin Endocrinol Metab, 2000 Sep;85:3431-5). This variant was also seen in compound heterozygosity with the p.R527H mutation in an individual with an atypical mandibulosacral dysplasia type A-like presentation (Lombardi F et al. J Clin Endocrinol Metab, 2007 Nov;92:4467-71). This variant has also been detected in the heterozygous state in a proband with Hutchinson-Gilford progeria syndrome with scleroderma-like skin changes (Zhang S et al. J Eur Acad Dermatol Venereol, 2016 Mar;30:463-5), and in the heterozygous state in an individual with dilated cardiomyopathy; however, two relatives with this variant were unaffected (Møller DV et al. Eur J Heart Fail, 2009 Nov;11:1031-5). This variant was detected in an additional dilated cardiomyopathy case; however, additional LMNA variants were also detected (Martins E et al. Rev Port Cardiol, 2019 06;38:441-447). In in vitro studies, cell lines with both p.V440M and p.R527H displayed abnormal nuclear morphology; however, no significant anomalies were apparent in transfected cells with p.V440M alone (Lombardi F et al. J Clin Endocrinol Metab, 2007 Nov;92:4467-71). Another study indicated this variant may impact protein-protein interactions; however, relevance of this finding is unclear (Dittmer TA et al. Mol Biol Cell, 2014 May;25:1493-510). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000057268	SCV004124991	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996102	SCV004819129	uncertain significance	Primary dilated cardiomyopathy	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 440 of the LMNA protein and is located in the lamin tail domain that is involved in binding to DNA and other proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that cells carrying this variant in the compound heterozygous state display altered nuclear morphology and heterochromatin organization (PMID: 17848409) and that this variant may affect interaction with other proteins (PMID: 24623722). However, the clinical relevance of these observations is not known. This variant has also been reported in heterozygosity in 2 individuals with dilated cardiomyopathy (PMID: 19875404, 30871747) and in an individual affected with Hutchinson-Gilford progeria syndrome (PMID: 25371241). This variant has been reported in compound heterozygosity in an individual affected with Dunnigan-type partial lipodystrophy (PMID: 10999845) and in an individual affected with mandibuloacral dysplasia type A-like phenotype (PMID: 17848409). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
OMIM	RCV000015617	SCV000035882	pathogenic	Mandibuloacral dysplasia with type A lipodystrophy, atypical	2007-11-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057268	SCV000088381	not provided	not provided		no assertion provided	not provided