ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.1292C>T (p.Ser431Leu) (rs149846886)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493862 SCV000582255 uncertain significance not provided 2018-02-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ACTN2 gene. The S431L variant has not been previously published in association with cardiomyopathy to our knowledge. The S431L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the S431L variant is observed in 34/16406 (0.21%) alleles from individuals of South Asian ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Ambry Genetics RCV000618284 SCV000737063 uncertain significance Cardiovascular phenotype 2019-07-24 criteria provided, single submitter clinical testing The p.S431L variant (also known as c.1292C>T), located in coding exon 12 of the ACTN2 gene, results from a C to T substitution at nucleotide position 1292. The serine at codon 431 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001089299 SCV001008059 likely benign Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2020-10-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193479 SCV001362350 likely benign not specified 2019-08-05 criteria provided, single submitter clinical testing Variant summary: ACTN2 c.1292C>T (p.Ser431Leu) results in a non-conservative amino acid change located in the Spectrin repeat domain (IPR002017) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 251310 control chromosomes, predominantly at a frequency of 0.0018 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 72 fold of the estimated maximal expected allele frequency for a pathogenic variant in ACTN2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.1292C>T has been reported in the literature as a VUS in individuals affected with SIDS (Sahlin_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001193479 SCV001433248 likely benign not specified 2020-03-27 criteria provided, single submitter clinical testing

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