Submissions for variant NM_001105206.3(LAMA4):c.2171G>A (p.Arg724Lys)

gnomAD frequency: 0.00067  dbSNP: rs146868519

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172550	SCV000051392	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037349	SCV000061006	uncertain significance	not specified	2015-05-18	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Arg717Lys var iant in LAMA4 has been identified by our laboratory in 1 individual with DCM wit h LBBB and in 1 individual with a family history of ARVC. This variant has also been identified in 0.1% (92/66738) of European chromosomes by the Exome Aggregat ion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs146868519). Comput ational prediction tools and conservation analysis suggest that the p.Arg717Lys variant may not impact the protein and 2 species (green sea turtle and tasmanian devil) carry a lysine (Lys) at this position suggesting this change may be tole rated. However, this information is not predictive enough to rule out pathogenic ity. This variant is located in the last three bases of the exon, which is part of the 5? splice region. Computational tools do not suggest an impact to splicin g. However, this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Arg717Lys variant is uncer tain, these data suggest that it is more likely to be benign.
GeneDx	RCV000037349	SCV000250530	uncertain significance	not specified	2017-01-26	criteria provided, single submitter	clinical testing	Although the R717K variant in the LAMA4 gene has not been published as pathogenic or been reported as benign to our knowledge, it has been reported as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000061006.3; Landrum et al., 2016), and has been reported as likely benign in the ClinSeq Project (Ng et al., 2013). This variant has been observed in 0.1-0.2% of alleles from individuals of European ancestry in large population cohorts (Lek et al., 2016; Exome Variant Server). The R717K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Although this substitution occurs at a position conserved in mammals, in silico analysis predicts this variant likely does not alter the protein structure/function.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000528892	SCV000604089	likely benign	Dilated cardiomyopathy 1JJ	2022-04-21	criteria provided, single submitter	clinical testing
Invitae	RCV000528892	SCV000654004	likely benign	Dilated cardiomyopathy 1JJ	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618226	SCV000735423	likely benign	Cardiovascular phenotype	2018-02-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770214	SCV000901644	uncertain significance	Cardiomyopathy	2017-04-11	criteria provided, single submitter	clinical testing
Klaassen Lab, Charite University Medicine Berlin	RCV000853135	SCV000995847	uncertain significance	Primary dilated cardiomyopathy	2019-07-03	criteria provided, single submitter	research
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000528892	SCV003920142	uncertain significance	Dilated cardiomyopathy 1JJ	2021-03-30	criteria provided, single submitter	clinical testing	LAMA4 NM_002290.4 exon 17 p.Arg717Lys (c.2150G>A): This variant has not been reported in the literature and is present in 0.1% (163/129082) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/6-112471715-C-T). This variant is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:44361). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003924918	SCV004737625	likely benign	LAMA4-related disorder	2022-04-04	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037349	SCV004803573	likely benign	not specified	2024-01-22	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000528892	SCV000734446	likely benign	Dilated cardiomyopathy 1JJ		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172550	SCV001930629	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172550	SCV001959003	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172550	SCV001973384	likely benign	not provided		no assertion criteria provided	clinical testing