Submissions for variant NM_003673.4(TCAP):c.60C>G (p.Ala20=)

gnomAD frequency: 0.00034  dbSNP: rs146502276

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037801	SCV000061463	likely benign	not specified	2015-07-07	criteria provided, single submitter	clinical testing	p.Ala20Ala in exon 1 of TCAP: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 34/66232 European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org/; dbSNP rs146502276).
Eurofins Ntd Llc (ga)	RCV000723762	SCV000112241	uncertain significance	not provided	2016-12-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081526	SCV000253398	likely benign	Hypertrophic cardiomyopathy 25; Primary familial hypertrophic cardiomyopathy	2025-01-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000037801	SCV000309782	likely benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000248291	SCV000320373	likely benign	Cardiovascular phenotype	2015-11-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000385933	SCV000402544	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2G	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000275117	SCV000402545	uncertain significance	Hypertrophic cardiomyopathy 25	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000037801	SCV000514862	benign	not specified	2015-04-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CeGaT Center for Human Genetics Tuebingen	RCV000723762	SCV001250273	likely benign	not provided	2025-02-01	criteria provided, single submitter	clinical testing	TCAP: BP4, BP7
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037801	SCV001363978	benign	not specified	2019-04-16	criteria provided, single submitter	clinical testing	Variant summary: TCAP c.60C>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00029 in 251058 control chromosomes (gnomAD). The observed variant frequency is approximately 12 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. Though c.60C>G has been reported in the literature in an individual affected with Dilated Cardiomyopathy (DCM), this patient also had a co-occurring pathogenic variant (TNNT2 c.629_631delAGA (p.Lys210del)) that could explain the reported phenotype, providing supporting evidence for a benign role for the variant of interest. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant three times as likely benign, twice as uncertain significance, and once as benign. Based on the evidence outlined above, the variant was classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000723762	SCV001744679	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000723762	SCV001952447	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000723762	SCV001968402	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000037801	SCV001979048	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000723762	SCV002034087	likely benign	not provided		no assertion criteria provided	clinical testing