ClinVar Miner

Submissions for variant NM_001105206.3(LAMA4):c.2171G>A (p.Arg724Lys) (rs146868519)

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Total submissions: 9
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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,Partners HealthCare 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 RCV000172550 SCV000604089 uncertain significance not provided 2017-06-07 criteria provided, single submitter clinical testing The p.Arg717Lys variant (rs146868519) is listed in the NHLBI GO Exome Sequencing Project (ESP) with an overall allele frequency of 0.11% (identified in 14 out of 13,006 chromosomes), and in the Exome Aggregation Consortium (ExAC) browser with an overall frequency of 0.08% (identified in 101 out of 121,506 chromosomes). It is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 44361), although it also has been previously classified as likely benign following an analysis suggesting that its population frequency precludes a pathogenic role in dilated cardiomyopathy (Ng 2103). The arginine at codon 717 is weakly conserved considering 12 species (Alamut software v2.8.1), and computational analyses suggest this variant does not have a significant effect on LAMA4 protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Arg717Lys variant cannot be determined with certainty.
Invitae RCV000528892 SCV000654004 likely benign Dilated cardiomyopathy 1JJ 2017-11-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618226 SCV000735423 likely benign Cardiovascular phenotype 2018-02-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Subpopulation frequency in support of benign classification
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
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000528892 SCV000734446 likely benign Dilated cardiomyopathy 1JJ no assertion criteria provided clinical testing

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