Submissions for variant NM_170707.4(LMNA):c.949G>A (p.Glu317Lys)

gnomAD frequency: 0.00001  dbSNP: rs56816490

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041379	SCV000065072	likely pathogenic	Primary dilated cardiomyopathy	2022-09-09	criteria provided, single submitter	clinical testing	The p.Glu317Lys variant in LMNA has been reported in at least 5 individuals with DCM and arrhythmia (atrioventricular (AV) block) and in 2 individuals with DCM and segregated with disease in at least 3 affected relatives from 3 families (Arbustini 2002 PMID: 11897440, Pasotti 2008 PMID: 18926329, Millat 2009 PMID: 19318026, Morales 2020 PMID: 32160020, LMM data). This variant has also been identified in 1 individual with AV block and a family history of sudden cardiac death (LMM data) and in a large family with isolated AV block, including one proband and 5 segregations (Villa 2014 PMID: 25469153). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 48093) and has also been identified in 0.001% (1/68028) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Variants in LMNA are prevalent in individuals with DCM and conduction system disease/arrhythmia and the presence of conduction system disease in the majority of affected individuals with this variant increases the likelihood that it is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PS4_Moderate, PP1_Moderate, PP3, PM2_Supporting.
GeneDx	RCV000057489	SCV000234687	pathogenic	not provided	2022-08-29	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27532257, 25469153, 34768595, 18926329, 12898247, 11897440, 19318026, 28759816, 28679633, 30420677, 21846512, 10939567, 31514951, 30287275, 32686758, 32160020, 24503780, 34862408, 34616814, 34773379)
Invitae	RCV000560270	SCV000657829	pathogenic	Charcot-Marie-Tooth disease type 2	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 317 of the LMNA protein (p.Glu317Lys). This variant is present in population databases (rs56816490, gnomAD 0.007%). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 11897440, 21846512, 25469153, 27532257; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48093). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769726	SCV000901147	likely pathogenic	Cardiomyopathy	2016-06-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000784	SCV001157842	likely pathogenic	not specified	2018-09-25	criteria provided, single submitter	clinical testing	The LMNA c.949G>A; p.Glu317Lys variant (rs56816490), is reported in the literature in multiple individuals and families affected with dilated cardiomyopathies (DCM) and atrioventricular block with DCM (Arbustini 2002, Millat 2009, Pasotti 2008, Villa 2014, Walsh 2017). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 48093) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamic acid at codon 317 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Glu317Lys variant is considered to be likely pathogenic. References: Arbustini E et al. Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. J Am Coll Cardiol. 2002 Mar 20;39(6):981-90. Millat G et al. Validation of high-resolution DNA melting analysis for mutation scanning of the LMNA gene. Clin Biochem. 2009 Jun;42(9):892-8. Pasotti M et al. Long-term outcome and risk stratification in dilated cardiolaminopathies. J Am Coll Cardiol. 2008 Oct 7;52(15):1250-60. Villa F et al. A G613A missense in the Hutchinson's progeria lamin A/C gene causes a lone, autosomal dominant atrioventricular block. Immun Ageing. 2014 Nov 26;11(1):19. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251293	SCV001426830	pathogenic	Primary familial dilated cardiomyopathy	2023-10-02	criteria provided, single submitter	clinical testing	Variant summary: LMNA c.949G>A (p.Glu317Lys) results in a conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248396 control chromosomes (gnomAD). c.949G>A has been reported in the literature in multiple individuals and families affected with Dilated Cardiomyopathy (DCM) or DCM and atrioventricular block (AVB) or AVB alone; co-segregation with disease was documented within different families (e.g. Arbustini_2002, Pasotti_2008, Millat_2011, Villa_2014, Walsh_2017). The following publications have been ascertained in the context of this evaluation (PMID: 11897440, 21846512, 18926329, 25469153, 27532257). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Athena Diagnostics	RCV000057489	SCV001880742	pathogenic	not provided	2021-04-07	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant segregates with disease in at least one family. Computational tools predict that this variant is damaging.
AiLife Diagnostics, AiLife Diagnostics	RCV000057489	SCV002503106	likely pathogenic	not provided	2020-06-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371856	SCV002688218	pathogenic	Cardiovascular phenotype	2023-08-10	criteria provided, single submitter	clinical testing	The p.E317K pathogenic mutation (also known as c.949G>A), located in coding exon 6 of the LMNA gene, results from a G to A substitution at nucleotide position 949. The glutamic acid at codon 317 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in multiple individuals with dilated cardiomyopathy and/or atrioventricular block (AVB) or other arrhythmia, and has shown strong segregation with disease in a large Italian family with AVB (Arbustini E et al. J. Am. Coll. Cardiol. 2002;39:981-90; Pasotti M et al. J. Am. Coll. Cardiol. 2008;52:1250-60; Millat G et al. Eur J Med Genet. 2011;54:e570-5; Pugh TJ et al. Genet. Med. 2014;16:601-8; Villa F et al. Immun Ageing. 2014;11:19; Walsh R et al. Genet. Med., 2017 02;19:192-203; Captur G et al. Eur. J. Heart Fail., 2018 10;20:1413-1416; Kwapich M et al. Diabetes Metab., 2019 09;45:382-389; van Tienen FHJ et al. Eur. J. Hum. Genet., 2019 03;27:389-399). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
New York Genome Center	RCV001775075	SCV003925444	pathogenic	Dilated cardiomyopathy 1A	2022-04-22	criteria provided, single submitter	clinical testing	The c.949G>A variant has previously been reported in individuals with dilated cardiomyopathy [PMID: 34768595, 32686758, 32160020, 31514951, 21846512,27532257]. The variant has also been identified in multiple individuals with dilated cardiomyopathy with atrioventricular block [PMID: 11897440, 25469153]. Moreover, this variant has been shown to segregate with the isolated atrioventricular block in a large family [PMID: 25469153] and it has been deposited in ClinVar [ClinVar ID:48093] as Pathogenic and Likely Pathogenic by multiple submitters. The c.949G>A variant is observed in 4 alleles (0.00086% 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. The c.949G>A variant is located in exon 6 of this 12-exon gene and is predicted to replace an evolutionarily conserved glutamic acid amino acidwith lysine at position 317 in the coil 2B domain of the encoded protein. In silico predictions are in favor of damaging effect for (p.Glu317Lys) (CADD v1.6 = 34, REVEL =0.873); however, there are no functional studies to support or refute these predictions. Based on available evidence this c.949G>A (p.Glu317Lys) variant identified in LMNA is classified here as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004541210	SCV004771965	pathogenic	LMNA-related disorder	2023-10-18	criteria provided, single submitter	clinical testing	The LMNA c.949G>A variant is predicted to result in the amino acid substitution p.Glu317Lys. This variant has been reported in multiple individuals with dilated cardiomyopathy or atrioventricular blockage and has also segregated within families (Table 1, Arbustini et al. 2002. PubMed ID: 11897440; Figure 1, Villa et al. 2014. PubMed ID: 25469153; Figure 2, Ferradini et al. 2021. PubMed ID: 34768595). This variant has been reported as a possible Italian founder variant (Ferradini et al. 2021. PubMed ID: 34768595). This variant is reported in 0.0065% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-156105704-G-A). This variant is interpreted as pathogenic for autosomal dominant LMNA-related disorders.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057489	SCV000088603	not provided	not provided		no assertion provided	not provided
Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University	RCV001775075	SCV001593109	pathogenic	Dilated cardiomyopathy 1A	2021-04-27	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000057489	SCV001742448	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000057489	SCV001920681	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000057489	SCV001932491	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000057489	SCV001951554	likely pathogenic	not provided		no assertion criteria provided	clinical testing