ClinVar Miner

Submissions for variant NM_003673.3(TCAP):c.209G>A (p.Arg70Gln) (rs552865793)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000183928 SCV000341583 uncertain significance not provided 2016-04-20 criteria provided, single submitter clinical testing
GeneDx RCV000183928 SCV000236416 likely pathogenic not provided 2014-08-28 criteria provided, single submitter clinical testing p.Arg70Gln (CGG>CAG): c.209 G>A in exon 2 of the TCAP gene (NM_003673.3). The R70Q variant that is likely pathogenic was identified in the TCAP gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R70Q variant was not observed in approximately 6,500 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 R70Q 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. One missense mutation in this same residue (R70W) has been reported in the association with HCM. The patient harboring the R70W variant was reported to have massive hypertrophy with a septal wall thickness of 46mm (Bos et. al., 2006). Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in CARDIOMYOPATHY panel(s).
Invitae RCV000793752 SCV000933121 uncertain significance Dilated cardiomyopathy 1N; Primary familial hypertrophic cardiomyopathy 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 70 of the TCAP protein (p.Arg70Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs552865793, ExAC 0.01%). This variant has not been reported in the literature in individuals with TCAP-related disease. ClinVar contains an entry for this variant (Variation ID: 202110). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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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