rs199476322
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP2BS2
The NM_001018005.2(TPM1):c.850A>G(p.Ile284Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,620 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I284T) has been classified as Uncertain significance.
Frequency
Consequence
NM_001018005.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPM1 | NM_001018005.2 | c.850A>G | p.Ile284Val | missense_variant, splice_region_variant | 9/10 | ENST00000403994.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPM1 | ENST00000403994.9 | c.850A>G | p.Ile284Val | missense_variant, splice_region_variant | 9/10 | 1 | NM_001018005.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461422Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 726932
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74360
ClinVar
Submissions by phenotype
not provided Uncertain:3Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 10, 2022 | 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) - |
not provided, no classification provided | curation | Leiden Muscular Dystrophy (TPM1) | Apr 15, 2012 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 12, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 09, 2014 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jul 08, 2015 | 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). - |
Hypertrophic cardiomyopathy Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 02, 2023 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | 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. - |
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 19, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 14, 2022 | - - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Genetics and Genomics Program, Sidra Medicine | - | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 26, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at