ClinVar Miner

Submissions for variant NM_003673.3(TCAP):c.421C>G (p.Pro141Ala) (rs45509691)

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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 RCV000620741 SCV000736326 uncertain significance Cardiovascular phenotype 2016-09-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Blueprint Genetics RCV000157513 SCV000207258 likely benign Cardiomyopathy 2014-06-16 no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725845 SCV000339898 uncertain significance not provided 2018-07-31 criteria provided, single submitter clinical testing
GeneDx RCV000725845 SCV000236419 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing The P141A variant of uncertain significance in the TCAP gene has previously been reported in a patient with idiopathic DCM who also harbored likely-disease causing variants in other genes (Hershberger et al., 2008; Hershberger et al., 2010). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P141A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge no studies have been performed to determine the functional effect of the P141A variant.
GenomeConnect, ClinGen RCV000845017 SCV000986849 not provided Limb-girdle muscular dystrophy, type 2G; Dilated cardiomyopathy 1N no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 08/01/2018 by GTR ID EGL Genetics. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000532216 SCV000639703 uncertain significance Dilated cardiomyopathy 1N; Primary familial hypertrophic cardiomyopathy 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 141 of the TCAP protein (p.Pro141Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs45509691, ExAC 0.006%). This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 19412328, 20215591). However, in one of those individuals, this variant was observed in unaffected relatives. ClinVar contains an entry for this variant (Variation ID: 180535). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. 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.

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