ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.82G>C (p.Asp28His) (rs397516391)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036364 SCV000060016 uncertain significance not specified 2017-12-01 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000766945 SCV000209347 uncertain significance not provided 2016-09-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TPM1 gene. The D28H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant has been observed in other unrelated individuals referred for HCM genetic testing at GeneDx, and was found to segregate with disease in at least one affected relative. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D28H 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 across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge no studies have been performed to determine the functional effect of the D28H variant. Furthermore, D28H has been classified in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar SCV000060016.4, SCV000220106.1; Landrum et al., 2016). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Ambry Genetics RCV000620750 SCV000736927 uncertain significance Cardiovascular phenotype 2017-09-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000689264 SCV000816906 uncertain significance Hypertrophic cardiomyopathy 2018-04-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 28 of the TPM1 protein (p.Asp28His). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 43444). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Asp28Asn) has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 24793961). A computational algorithm designed to assess the pathogenicity of variants in TPM1 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Blueprint Genetics RCV000766945 SCV000927987 likely pathogenic not provided 2018-10-11 criteria provided, single submitter clinical testing

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