ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.841A>G (p.Met281Val) (rs397516394)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036368 SCV000060020 uncertain significance not specified 2013-08-27 criteria provided, single submitter clinical testing The Met281Val variant in TPM1 has now been identified by our laboratory in 2 Cau casian individuals with HCM, though it did not segregate with disease in one aff ected relative. This variant has not been identified in large population studies . Conservation and other computational analyses are unreliable for this exon. Fi nally, another variant of unknown significance has been reported at this positio n in two patients with HCM (Met281Thr; Van Driest 2003, LMM unpublished data). I n summary, additional information is needed to fully assess the clinical signifi cance of this variant.
GeneDx RCV000766955 SCV000209335 uncertain significance not provided 2018-03-09 criteria provided, single submitter clinical testing The M281V variant of uncertain significance in the TPM1 gene has been previously observed in two studies including individuals with HCM but no further information was provided in the publications (Marston et al., 2013; Gomez et al., 2014). The M281V 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. Although this variant occurs at a position that is conserved across species, it results in a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in the same residue (M281T) has been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Nevertheless, another clinical laboratory has also classified this change as a variant of uncertain significance in the ClinVar Database (ClinVar SCV000060020.3; Landrum et al., 2016). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000553548 SCV000623815 uncertain significance Hypertrophic cardiomyopathy 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 281 of the TPM1 protein (p.Met281Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs397516394, ExAC 0.02%). This variant has been reported in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 28356264, 27532257, 28797094). ClinVar contains an entry for this variant (Variation ID: 43448). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Met281Thr) has been determined to be pathogenic (PMID: 12860912, 18533079, 20965760, 21835320, 22112859, 25524337, 25548289). This suggests that the methionine residue is critical for TPM1 protein function and that other missense substitutions at this position may also be pathogenic. 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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