Submissions for variant NM_001276345.2(TNNT2):c.544G>T (p.Ala182Ser)

gnomAD frequency: 0.00002  dbSNP: rs730881097

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000615596	SCV000710841	likely pathogenic	Primary dilated cardiomyopathy	2019-03-07	criteria provided, single submitter	clinical testing	The p.Ala172Ser variant in TNNT2 has been reported in 1 individual with DCM and segregated with disease in at least 4 affected relatives (Stefanelli 2004). Present in ClinVar (ID 18162) and gnomad 4/282894 total chromosomes. It has also been identified in 1/80 HCM patients by Viswanathan 2017. This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala172Ser variant is uncertain. ACMG/AMP Criteria applied: PM2, PP1, PP3.
Illumina Laboratory Services, Illumina	RCV000778960	SCV000915387	uncertain significance	Dilated cardiomyopathy 1D	2017-10-12	criteria provided, single submitter	clinical testing	The TNNT2 c.514G>T (p.Ala172Ser) missense variant (which has also been referred to as p.Ala171Ser) has been reported in two studies in which it was identified in a heterozygous state in at least nine clinically affected members of a large, multigenerational family affected by left ventricular dilatation, systolic dysfunction, and sudden cardiac death (Stefanelli et al. 2004). The p.Ala172Ser variant was also detected in an unrelated individual with dilated cardiomyopathy (Jáchymová et al. 2012). Three clinically indeterminate and three asymptomatic members of the large family also carried the variant. Within the family, male carriers of the variant had more severe symptoms, and two of them died suddenly (Stefanelli et al. 2004). The p.Ala172Ser variant was absent from 212 control individuals and is reported at a frequency of 0.000024 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies of the variant have not been conducted, but it affects a highly conserved residue in the alpha-tropomyosin binding domain (Stefanelli et al. 2004). Based on the limited evidence available, the p.Ala172Ser variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal dominant dilated cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001067821	SCV001232902	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 172 of the TNNT2 protein (p.Ala172Ser). This variant is present in population databases (rs730881097, gnomAD 0.004%). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM) (PMID: 15464434, 22292720, 29121657). It has also been observed to segregate with disease in related individuals. This variant is also known as A171S. ClinVar contains an entry for this variant (Variation ID: 181612). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function. Studies have shown that this missense change alters TNNT2 gene expression (PMID: 33025817). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV001101098	SCV001257669	uncertain significance	Hypertrophic cardiomyopathy 2	2017-10-11	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001101099	SCV001257670	uncertain significance	Cardiomyopathy, familial restrictive, 3	2017-10-11	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001185278	SCV001351453	likely pathogenic	Cardiomyopathy	2024-01-02	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 172 of the TNNT2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been shown to segregate with dilated cardiomyopathy in multiple affected individuals in two families (PMID: 15464434, 35653365). This variant has also been reported in two additional unrelated individuals affected with dilated cardiomyopathy (PMID: 22292720, 28008009) and two individuals affected with hypertrophic cardiomyopathy (PMID: 29121657, 35653365). This variant has been identified in 4/282894 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.