ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.457C>G (p.His153Asp) (rs397516372)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000527568 SCV000059985 likely pathogenic Hypertrophic cardiomyopathy 2014-01-16 criteria provided, single submitter clinical testing The His153Asp variant in TPM1 has been identified by our laboratory in 1 Caucasi an individual with HCM and segregated with disease in 2 affected relatives. It w as not identified in large population studies. Histidine (His) at position 153 i s highly conserved in mammals and across evolutionarily distant species and the change to aspartic acid (Asp) was predicted to be pathogenic using a computation al tool clinically validated by our laboratory. This tool's pathogenic predictio n is estimated to be correct 94% of the time (Jordan 2011). In summary, this var iant is likely pathogenic, though additional studies are required to fully estab lish its clinical significance.
Invitae RCV000527568 SCV000623804 uncertain significance Hypertrophic cardiomyopathy 2018-08-06 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 153 of the TPM1 protein (p.His153Asp). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 43419). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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