Submissions for variant NM_001267550.2(TTN):c.65776G>A (p.Val21926Met)

gnomAD frequency: 0.00093  dbSNP: rs145527033

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001704915	SCV000237434	likely benign	not provided	2019-01-16	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223513	SCV000271061	likely benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	p.Val19358Met in Exon 262 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.3% (11/3270) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs145527033).
Eurofins Ntd Llc (ga)	RCV000223513	SCV000332111	likely benign	not specified	2015-06-11	criteria provided, single submitter	clinical testing
Invitae	RCV000541875	SCV000643535	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001704915	SCV001471389	likely benign	not provided	2020-08-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000223513	SCV002572246	benign	not specified	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: TTN c.58072G>A (p.Val19358Met) results in a conservative amino acid change located in the A-band of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 245946 control chromosomes, predominantly at a frequency of 0.0029 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.58072G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four 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 likely benign. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002354502	SCV002621530	likely benign	Cardiovascular phenotype	2018-05-26	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486753	SCV004240065	benign	Cardiomyopathy	2023-01-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537550	SCV004731576	likely benign	TTN-related disorder	2021-03-02	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Clinical Genetics, Academic Medical Center	RCV000223513	SCV001925296	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001704915	SCV001958507	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001704915	SCV001969519	likely benign	not provided		no assertion criteria provided	clinical testing