Submissions for variant NM_000364.3(TNNT2):c.113C>T (p.Ala38Val)

gnomAD frequency: 0.00046  dbSNP: rs200754249

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036624	SCV000060279	benign	not specified	2018-03-15	criteria provided, single submitter	clinical testing	p.Ala28Val in exon 5 of TNNT2: This variant is classified as benign because it h as been identified in 0.07% (84/126672) of European chromosomes by the Genome Ag gregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200754249) . Furthermore, alanine (Ala) at position 28 is not conserved in mammals or evolu tionarily distant species and >10 mammals carry a valine (Val) at this position, supporting that this change may be tolerated. ACMG/AMP Criteria applied: BS1; B P4_Strong.
CSER _CC_NCGL, University of Washington	RCV000148900	SCV000190646	uncertain significance	Increased left ventricular wall thickness	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx	RCV000588568	SCV000209275	likely benign	not provided	2021-06-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24055113, 22017532, 21846512, 23233322, 24503780, 23299917, 25637381, 19645627, 16754800, 22464770, 27153395, 27600940, 22455086, 22958901, 15631686, 30871747, 30122538, 25351510, 31019283, 27535533, 26582918, 32004434, 33025817)
Invitae	RCV001081698	SCV000541927	likely benign	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588568	SCV000697571	likely benign	not provided	2016-10-25	criteria provided, single submitter	clinical testing	Variant summary: The TNNT2 c.83C>T (p.Ala28Val) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 60/126398 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0006453 (43/66632). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic TNNT2 variant (0.00025), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. One internal sample also carried a pathogenic variant in MYBPC3 c.2308G>A/p.D770N and LMM cites the variant to co-occur in a patient with an unspecified pathogenic variant in another gene known to cause HCM, further supporting the non-pathogenicity of this variant. This variant has been reported in HCM and DCM patients without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as VUS/likely benign. LMM has classified the variant as likely benign, in part because of unpublished data from their lab showing the variant did not segregate with disease in 2 affected relatives from one family with DCM. Taken together, this variant is classified as likely benign until more evidence becomes available.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000755701	SCV000883135	uncertain significance	Dilated cardiomyopathy 1D	2018-11-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771256	SCV000903366	likely benign	Cardiomyopathy	2018-06-18	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852592	SCV000995294	likely benign	Supraventricular tachycardia	2017-10-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001099310	SCV001255755	uncertain significance	Hypertrophic cardiomyopathy 2	2018-02-21	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001099311	SCV001255756	uncertain significance	Cardiomyopathy, familial restrictive, 3	2018-02-21	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771256	SCV001333862	likely benign	Cardiomyopathy	2022-08-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433498	SCV002680244	likely benign	Cardiovascular phenotype	2019-04-22	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.
Evolutionary and Medical Genetics Laboratory, Centre for Cellular and Molecular Biology	RCV000149450	SCV000196094	pathogenic	Primary familial hypertrophic cardiomyopathy		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Clinical Genetics, Academic Medical Center	RCV000588568	SCV001918868	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000588568	SCV001931251	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000036624	SCV001952596	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000588568	SCV001962784	likely benign	not provided		no assertion criteria provided	clinical testing