Submissions for variant NM_003280.3(TNNC1):c.210C>T (p.Gly70=)

gnomAD frequency: 0.00010  dbSNP: rs141505676

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037761	SCV000061423	likely benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	Gly70Gly in exon 4 of TNNC1: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 2/7020 European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs141505676). Gly70Gly in exon 4 of TNNC 1 (rs141505676; allele frequency = 2/7020) **
Illumina Laboratory Services, Illumina	RCV000262457	SCV000445499	uncertain significance	Hypertrophic cardiomyopathy 13	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	RCV000322551	SCV000445500	uncertain significance	Dilated cardiomyopathy 1Z	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555960	SCV000648285	likely benign	Dilated cardiomyopathy 1Z; Hypertrophic cardiomyopathy 13	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001355522	SCV001939213	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798117	SCV002043225	uncertain significance	Cardiomyopathy	2019-09-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415471	SCV002729749	likely benign	Cardiovascular phenotype	2017-06-29	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.
CeGaT Center for Human Genetics Tuebingen	RCV001355522	SCV004034003	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	TNNC1: BP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355522	SCV001550434	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TNNC1 p.Gly70Gly variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs141505676) and ClinVar (classified as uncertain significance by Illumina and Invitae and as likely benign by Laboratory for Molecular Medicine). The variant was identified in control databases in 32 of 282728 chromosomes at a frequency of 0.0001132 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 30 of 129090 chromosomes (freq: 0.000232), Other in 1 of 7220 chromosomes (freq: 0.000139) and East Asian in 1 of 19952 chromosomes (freq: 0.00005), but was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish), or South Asian populations. The p.Gly70Gly variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. However, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 5' splice site. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.