ClinVar Miner

Submissions for variant NM_003476.5(CSRP3):c.536C>T (p.Thr179Met) (rs142019584)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150366 SCV000197489 uncertain significance not specified 2013-08-23 criteria provided, single submitter clinical testing The Thr179Met variant in CSRP3 has not been previously reported in individuals w ith cardiomyopathy but has been identified in 1/8586 of European American chromo somes and 1/4398 of African American chromosomes by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS/; dbSNP rs142019584). Computational ana lyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, an d SIFT) do not provide strong support for or against an impact to the protein. A dditional information is needed to fully assess the clinical significance of the Thr179Met variant. The Thr179Met variant in CSRP3 (allele frequency=1/8586 of European American chromosomes and 1/4398 of African American; dbSNP rs142019584) **
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000201497 SCV000256190 likely pathogenic Familial hypertrophic cardiomyopathy 12 criteria provided, single submitter clinical testing
Invitae RCV000231901 SCV000287948 uncertain significance Familial hypertrophic cardiomyopathy 12; Dilated cardiomyopathy 1M 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 179 of the CSRP3 protein (p.Thr179Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs142019584, ExAC 0.01%) but has not been reported in the literature in individuals with a CSRP3-related disease. ClinVar contains an entry for this variant (Variation ID: 163007). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786289 SCV000925050 uncertain significance not provided 2017-06-26 no assertion criteria provided provider interpretation p.Thr179Met (c.536C>T) in exon 7 of the CSRP3 gene (NM_003476.4) Given the weak case data and presence in the general population, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 2 unrelated cases of hypertrophic cardiomyopathy (not including this patient's family). There is no case data. This variant is present in ClinVar. It is classified as a variant of uncertain significance by LMM and likely pathogenic by the Laboratory of Genetics and Molecular Cardiology, University of São Paulo - Sarcomeric Human Cardiomyopathy Registry (ShaRe). LMM has seen this variant once in one individual. Per the test report, "algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0")." The threonine at codon 179 is weakly conserved across species. No other variants have been reported in association with disease at this codon or nearby codons. The variant was reported online in 9 of 123,067 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 5 of 7,652 individuals of African descent (MAF=0.033%), 3 of 16,790 individuals of Latino descent and 1 of 2,741 individuals of "other" descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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