ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.715G>A (p.Ala239Thr) (rs199476318)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000471524 SCV000547691 uncertain significance Hypertrophic cardiomyopathy 2018-03-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 239 of the TPM1 protein (p.Ala239Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (rs199476318, ExAC no frequency). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 20215591, Invitae) and hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 31895). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance 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: "Probably Damaging"; Align-GVGD: "Class C0"). Missense variants that are absent from the ExAC population database have been shown to be significantly overrepresented in individuals with hypertrophic and dilated cardiomyopathy (PMID: 27532257).
Leiden Muscular Dystrophy (TPM1) RCV000024591 SCV000045900 not provided not provided 2012-04-15 no assertion provided curation
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000024591 SCV000924969 uncertain significance not provided 2017-05-24 no assertion criteria provided provider interpretation GENETIC TEST RESULTS This patient was diagnosed with DCM at age 5 months and underwent heart transplant at age 3 years. She had an Arrhythmia and Cardiomyopathy Comprehensive Panel with the Invitae laboratory. The following 120 genes were evaluated for sequence changes and exonic deletions/duplications: ABCC9, ACADVL, ACTC1, ACTN2, AGL, AKAP9, ALMS1, ANK2, ANKRD1, BAG3, CACNA1C, CACNA2D1, CACNB2, CALM1, CALM2, CALM3, CALR3, CASQ2, CAV3, CHRM2, CPT2, CRYAB, CSRP3, CTF1, CTNNA3, DES, DMD, DNAJC19, DOLK, DSC2, DSG2, DSP, DTNA, ELAC2, EMD, EYA4, FHL1, FHL2, FKRP, FKTN, FLNC, GAA, GATA4, GATA6, GATAD1, GJA5, GLA, GPD1L, HCN4, ILK, JPH2, JUP, KCNA5, KCND3, KCNE1, KCNE2, KCNE3, KCNE5, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNK3, KCNQ1, LAMA4, LAMP2, LDB3, LMNA, LRRC10, MTO1, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYL4, MYLK2, MYOM1, MYOZ2, MYPN, NEBL, NEXN, NKX2-5, NPPA, PDLIM3, PKP2, PLEKHM2, PLN, PRDM16, PRKAG2, RAF1, RANGRF, RBM20, RYR2, SCN10A, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SGCD, SLC22A5, SLMAP, SNTA1, TAZ, TCAP, TGFB3, TMEM43, TMEM70, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRDN, TRPM4, TTN, TTR, TXNRD2, VCL The following gene was evaluated for sequence changes only: SDHA. Results show that two variants were detected: · p.Ala239Thr (A239T; c.715G>A) in the TPM1 gene · p.Ser52Cys (S52C; c.155C>G) in the ELAC2 gene We suspect that the TPM1 variant may play a role in this patient’s heart condition, although there is not yet enough evidence to say that with certainty. p.Ala239Thr (A239T; c.715G>A) in exon 8 of the TPM1 gene (NM_001018005.1) Chromosome position: 15:63354787 G / A Based on the information reviewed below, we classify Ala239Thr as a VUS, probably disease-causing, concluding that there is not sufficient evidence at this time for its pathogenicity to warrant using it for predictive genetic testing. However, we do feel it is a good candidate to be pathogenic, and we plan to do additional testing to see if it is de novo in our patient. This variant has previously been reported in at least 2 unrelated individuals with cardiomyopathy. There is no published segregation data. It was reported by Hershberger et al. (2010) in an individual with familial dilated cardiomyopathy (PMID: 20215591). It was reported by Walsh et al. (2016) in an individual with hypertrophic cardiomyopathy who was sequenced at the Oxford Medical Genetics Laboratory (PMID: 27532257). It has not been submitted to ClinVar by a clinical testing laboratory as of December 12, 2016. This is a nonconservative amino acid change, resulting in the replacement of a nonpolar Alanine with a polar Threonine. Alanine at this location is absolutely conserved across ~100 vertebrate species for which we have data, as are multiple surrounding residues. According to the Invitae report, in silico algorithms do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A nearby missense variant (+/- 10 amino acids) has been submitted to ClinVar by multiple laboratories as solidly Pathogenic for dilated cardiomyopathy: p.Asp230Asn. The molecule is in a coiled coil structure that is formed by 2 polypeptide chains in close association with actin. The sequence exhibits a prominent seven-residues periodicity. In total the variant has not been seen in >140,000 published controls and individuals from publicly available population datasets. The variant was not observed in 246 published controls from multiple ethnicities (Hershberger et al. 2010). There is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. This variant is not present in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian). These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases. There is good coverage at this site: Almost all individuals are covered at 30x, with mean coverage of 80x and median coverage of 90x. This variant is also not present in the gnomAD database, which is an expansion of ExAC to include variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Our patient’s ancestry is African American.

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