ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs199476322
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham 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
GeneDx RCV000024594 SCV000209337 uncertain significance not provided 2022-01-10 criteria provided, single submitter clinical testing Reported in multiple individuals with HCM, sometimes referred to as M284V due to alternate nomenclature (Olivotto et al., 2008; Predmore et al., 2010; Witjas-Paalberends et al., 2013; Helms et al., 2014; Walsh et al., 2017; van Lint et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Functional studies demonstrated this variant did not perform significantly different compared to wildtype (Matyushenko et al., 2019); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#31898; ClinVar); This variant is associated with the following publications: (PMID: 30847666, 34681814, 27532257, 20159828, 33129908, Syomin2020, 18533079, 23674513, 25031304, 30240712)
Labcorp Genetics (formerly Invitae), Labcorp RCV000699606 SCV000828325 likely pathogenic Hypertrophic cardiomyopathy 2023-12-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 284 of the TPM1 protein (p.Ile284Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy and/or TPM1-related conditions (PMID: 18533079, 23674513, 25031304, 27532257, 30847666; Invitae). This variant is also known as p.Met284Val. ClinVar contains an entry for this variant (Variation ID: 31898). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TPM1 function (PMID: 30240712). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV001186001 SCV001352326 uncertain significance Cardiomyopathy 2023-10-19 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 284 of the TPM1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not have significant effects on protein function and interaction with actin (PMID: 30240712). This variant has been reported in seven individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 20159828, 23674513, 25031304, 27532257, 30847666), and in one individual with non-compaction cardiomyopathy (PMID: 30847666). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Genetics and Genomics Program, Sidra Medicine RCV001293088 SCV001434071 uncertain significance Primary dilated cardiomyopathy criteria provided, single submitter research
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001186001 SCV003838600 uncertain significance Cardiomyopathy 2022-03-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV003298036 SCV003999964 uncertain significance Cardiovascular phenotype 2023-04-26 criteria provided, single submitter clinical testing The p.I284V variant (also known as c.850A>G), located in coding exon 9 of the TPM1 gene, results from an A to G substitution at nucleotide position 850. The isoleucine at codon 284 is replaced by valine, an amino acid with highly similar properties. This alteration has been detected in patients reported to have hypertrophic cardiomyopathy, though in some cases clinical details were limited, and patient reports may overlap (Olivotto I et al. Mayo Clin Proc. 2008;83:630-8; Predmore JM et al. Circulation. 2010;121:997-1004; Witjas-Paalberends ER et al. Cardiovasc Res. 2013;99:432-41; Helms AS et al. Circ Cardiovasc Genet. 2014;7:434-43; Ho CY et al. Circulation, 2018 Oct;138:1387-1398). Functional studies have suggested this amino acid substitution may potentially impact protein function and myofibril force generation; however, the clinical relevance of this result is unclear (Sequeira V et al. Circ Res. 2013;112:1491-505; Witjas-Paalberends ER et al. Cardiovasc Res. 2013;99:432-41). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000152124 SCV004122798 uncertain significance not specified 2023-10-12 criteria provided, single submitter clinical testing Variant summary: TPM1 c.850A>G (p.Ile284Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250272 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.850A>G has been reported in the literature in individuals affected with hypertrophic cardiomyopathy, dilated cardiomyopathy, or non-compaction cardiomyopathy, without evidence of causality and often reported as a VUS (e.g. Olivotto_2008, Witjas-Paalberends_2013, Helms_2014, Ho_2018, vanWaning_2018, vanLint_2019, Al-Shafai_2021). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34137518, 25031304, 30297972, 18533079, 23674513, 30847666, 29447731). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=9) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health RCV000699606 SCV004815472 uncertain significance Hypertrophic cardiomyopathy 2024-07-23 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 284 of the TPM1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not have significant effects on protein function and interaction with actin (PMID: 30240712). This variant has been reported in seven individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 20159828, 23674513, 25031304, 27532257, 30847666), and in one individual with non-compaction cardiomyopathy (PMID: 30847666). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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).
Clinical Genetics, Academic Medical Center RCV000024594 SCV001924598 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000024594 SCV001972351 uncertain significance not provided no assertion criteria provided clinical testing

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