ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.850A>G (p.Ile284Val) (rs199476322)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000024594 SCV000209337 uncertain significance not provided 2017-11-07 criteria provided, single submitter clinical testing The I284V variant in the TPM1 gene has been reported previously in at least 2 individuals with HCM (Predmore J et al., 2010; Witjas-Paalberends E et al., 2013). The I284V 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. Furthermore, missense mutations in nearby residues (N279H, M281T) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Nevertheless, the I284V variant is a conservative amino acid substitution at the terminal residue of the TPM1 gene, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved across species.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in HCM panel(s).
Invitae RCV000699606 SCV000828325 uncertain significance Hypertrophic cardiomyopathy 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 284 of the TPM1 protein (p.Ile284Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (rs199476322, ExAC no frequency). This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 23674513, 25031304, 27532257). This variant is also known as p.Met284Val in the literature. ClinVar contains an entry for this variant (Variation ID: 31898). A computational algorithm designed to assess the pathogenicity of variants in TPM1 with regard to hypertrophic cardiomyopathy predicted this sequence change to be tolerated. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000152124 SCV000200813 uncertain significance not specified 2014-12-09 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Leiden Muscular Dystrophy (TPM1) RCV000024594 SCV000045903 not provided not provided 2012-04-15 no assertion provided curation
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000152124 SCV000280548 uncertain significance not specified 2015-07-08 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ile284Val (c.850A>G) in the TPM1 gene. To date this variant has been reported in two unrelated cases of HCM. Olivotto et al (2008) observed p.Ile284Val in one patient with HCM in a cohort recruited from Florence and Rome. Predmore et al (2010) reported the variant in an individual with HCM from an American clinic who had clinical genetic testing at LMM Laboratories. There is no segregation data available for the variant. This is a conservative amino acid change with a nonpolar Isoleucine replaced with a nonpolar Valine, at a position that is not conserved across species. Variants in nearby codons (p.Met281Thr, p.Thr282Ser (we classify as a variant of uncertain significance), p.Asp230Asn) have been reported in association with cardiomyopathy (Stenson P et al 2009, SCICD Cardiovascular database). This variant is in the second to last codon of the tropomyosin protein. In total the variant has not been seen in ~6650 published controls and publicly available general population samples. Olivotto et al (2008) report that the variant was absent in 150 presumably healthy Caucasian controls. The variant is not listed in dbSNP or 1000 Genomes. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 Caucasian and African American individuals (as of December 2012).

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