Submissions for variant NM_003673.4(TCAP):c.113G>T (p.Cys38Phe)

gnomAD frequency: 0.00005  dbSNP: rs375310569

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487833	SCV000236414	uncertain significance	not provided	2023-12-07	criteria provided, single submitter	clinical testing	Reported in published literature in a Middle Eastern child with suspected Duchenne's muscular dystrophy who also harbored additional cardiogenetic variants, including an in-frame deletion of DMD gene, and in an individual with HCM who also harbored additional cardiogenetic variants (PMID: 28482373, 32451364); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32451364, Schiava2022[paper], 37298070, 16490376, 28482373)
Eurofins Ntd Llc (ga)	RCV000487833	SCV000332594	uncertain significance	not provided	2016-12-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000487833	SCV000575100	uncertain significance	not provided	2017-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000560917	SCV000639691	uncertain significance	Hypertrophic cardiomyopathy 25; Primary familial hypertrophic cardiomyopathy	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 38 of the TCAP protein (p.Cys38Phe). This variant is present in population databases (rs375310569, gnomAD 0.03%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 32451364). ClinVar contains an entry for this variant (Variation ID: 202108). 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 disruptive. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000660576	SCV000782688	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2G; Hypertrophic cardiomyopathy 25	2017-06-19	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000991354	SCV001142723	uncertain significance	Hypertrophic cardiomyopathy	2020-01-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797668	SCV002041659	likely benign	not specified	2021-11-22	criteria provided, single submitter	clinical testing	Variant summary: TCAP c.113G>T (p.Cys38Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 239770 control chromosomes. The observed variant frequency is approximately 4.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in TCAP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.113G>T has been reported in the literature in at-least one individual affected with autosomal recessive hypertrophic cardiomyopathy attributed to a homozygous pathogenic variant in the TRIM63 gene (example, Salazar-Mendiguchia_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. The co-occurrence with other pathogenic variant mentioned above (TRIM63, p.Gln247*), provides supporting evidence for a benign role due to an alternate molecular basis of disease (Salazar-Mendiguchia_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. However, none of the submitters cite the evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002453666	SCV002618260	uncertain significance	Cardiovascular phenotype	2023-08-17	criteria provided, single submitter	clinical testing	The p.C38F variant (also known as c.113G>T), located in coding exon 2 of the TCAP gene, results from a G to T substitution at nucleotide position 113. The cysteine at codon 38 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported as homozygous in an individual with atypical cerebral palsy (Nejabat M et al. Front Pediatr, 2021 Sep;9:734946). This amino acid position is not well 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.
Revvity Omics, Revvity	RCV000487833	SCV003827088	uncertain significance	not provided	2021-10-06	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000487833	SCV005198757	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000660576	SCV005645978	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2G; Hypertrophic cardiomyopathy 25	2024-04-15	criteria provided, single submitter	clinical testing