ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.677A>G (p.Lys226Arg)

dbSNP: rs730881144
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159380 SCV000209326 uncertain significance not provided 2012-03-05 criteria provided, single submitter clinical testing The Lys226Arg variant in the TPM1 gene has not been reported previously as a disease-causing mutation or as a rare benign polymorphism, to our knowledge. Although Lys226Arg results in a conservative amino acid substitution of one positively charged amino acid with another, the substitution occurs at a position that is highly conserved throughout evolution. The NHLBI ESP Exome Variant Server reports Lys226Arg was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Additionally, a mutation in a nearby codon (Asp230Asn) has been reported in association with dilated cardiomyopathy (DCM), supporting the functional importance of this region of the protein. Nevertheless, multiple in silico analyses provide conflicting predictions regarding the effect of this missense change on the protein structure/function. The variant is found in HCM panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV002516401 SCV003442953 uncertain significance Hypertrophic cardiomyopathy 2022-07-07 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with clinical features of TPM1-related conditions (PMID: 27532257, 30847666). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 226 of the TPM1 protein (p.Lys226Arg). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 181671). 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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