ClinVar Miner

Submissions for variant NM_003280.2(TNNC1):c.23C>T (p.Ala8Val) (rs267607125)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618084 SCV000740104 uncertain significance Cardiovascular phenotype 2016-12-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000159204 SCV000209150 likely pathogenic not provided 2018-05-14 criteria provided, single submitter clinical testing The A8V variant in the TNNC1 gene has been reported previously in an individual with hypertrophic cardiomyopathy, and functional studies have shown that the A8V mutation disrupts the Ca 2+ switch mechanism resulting in a more open N-domain conformation in both the apo and holo states, increases the Ca 2+ sensitivity of reconstituted thin filaments and also enhances the effect of cTnI pseudo-phosphorylation on the rate of calcium dependence of actomyosin ATPase (Landstrom et al., 2008; Cordina et al., 2013; Albury et al., 2012). The A8V variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A8V variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. Based on currently available data, we consider A8V to be a strong candidate for a pathogenic variant; however, the possibility that it may be a rare benign variant cannot be excluded
Invitae RCV000013256 SCV000648283 likely pathogenic Familial hypertrophic cardiomyopathy 13 2017-02-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 8 of the TNNC1 protein (p.Ala8Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (rs267607125, ExAC no frequency). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 18572189, Invitae). It has also been observed in two siblings with infantile onset restrictive cardiomyopathy who were compound heterozygous with a second variant in TNNC1, although both heterozygous parents were asymptomatic (PMID: 27604170). ClinVar contains an entry for this variant (Variation ID: 12443). Experimental studies have shown that this missense change affects the response of reconstituted thin filaments to calcium upon cTnI phosphorylation (PMID: 18572189, 19439414, 21056975, 20459070, 22489623, 23425245, 26304555). In summary, this variant is absent from population databases, has been seen in several affected individuals, and has a deleterious effect on protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037762 SCV000061424 uncertain significance not specified 2014-07-30 criteria provided, single submitter clinical testing The Ala8Val variant in TNNC1 has been reported in one heterozygous Caucasian individual with HCM (Landstrom 2008) and has been identified by our laboratory in one homozygous child with RCM. Data from large population studies is insufficient to assess the frequency of this variant. In vitro functional studies indicate this variant may lead to altered calcium sensitivity of muscle cells, consistent with effects that have been established for other disease-associated variants (Landstrom 2008, Pinto 2009, Swindle 2010, Pinto 2011, Albury 2012, Cordina 2013). However, in vitro assays may not accurately represent biological function. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In addition, this variant is located in the last three bases of the exon, which is part of the 5’ splice region. Computational tools do not provide strong evidence for or against an impact to splicing. In summary, the clinical significance of the Ala8Val variant is uncertain.
OMIM RCV000013256 SCV000033503 pathogenic Familial hypertrophic cardiomyopathy 13 2008-08-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000037762 SCV000280500 uncertain significance not specified 2015-01-21 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.Ala8Val (c. 23 C>T) in TNNC1 Given the lack of case data and the somewhat tenuous link between HCM and TNNC1, we classify it as a variant of uncertain significance. This variant has been reported in one individual with HCM; he was diagnosed at 33 and had no family history of SCD or HCM (Landstrom et al 2008). To the best of our knowledge there are no other published reports of this variant in HCM. There is also no segregation data available on this variant. Only a handful of variants in TNNC1 have been reported in association with HCM and some groups question whether there is sufficient evidence supporting the link between HCM and TNNC1. Interestingly, from the paper that first reported this variant we are able to get data on the prevalence of TNNC1 variants in patients with HCM, which we can then compare to the prevalence of such variants in the general population. Landstrom et al (2008) sequenced TNNC1 in 1025 patients with HCM and identified rare missense variants (including this one) in 4 individuals (i.e. ~0.4%). Of note, in a general population sample, 0.1% of individuals had a rare or unique missense variant in TNNC1 (from the NHLBI ESP data set). Landstrom et al (2008) showed that specific missense mutations occurring in TNNC1, including this p.Ala8Val variant, show increased Ca2+ sensitivity of force development and force recovery. However, a subsequent paper from the same group noted that this variant was associated with diminished Ca2+ sensitivity (Pinto et al 2009). Swindle et al (2010) reported that p.Ala8Val did not affect the calcium or magnesium binding properties of the C-domain and it had no effects on binding of troponin C to troponin I. This variant occurs in the N-helix of the amino acid-terminal domain of the protein. The Alanine at codon 8 is completely conserved (Landstrom et al 2008). PolyPhen2 predicts the variant to be possibly damaging. It is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~5,300 Caucasian and African American individuals (as of May 2012). It is also not currently listed in dbSNP or 1000 genomes (as of May 2012). Landstrom et al (2008) did not observe the variant in 500 general population samples. p. Asp464Asn (c. 1390 G>A) in PRKAG2 Genetic testing also identified another variant of unknown significance in the PRKAG2 gene, Asp464Asn (c. 1390 G>A). This variant is novel. This results in a non-conservative amino acid change, where a negatively-charged amino acid (Aspartic Acid) is changed to a neutral, polar amino acid (Asparagine). This variant is predicted to be benign by PolyPhen-2 analysis. This residue is conserved across species. No other disease-causing variants have been reported at this or nearby codons. The variant was not observed in 313 individuals of various ethnic backgrounds at GeneDx. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~5,000 Caucasian and African American individuals (as of May 2012). The variant is not listed in dbSNP or 1000 genomes (as of May 2012).

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