Submissions for variant NM_001267550.2(TTN):c.102657T>A (p.Ser34219Arg)

gnomAD frequency: 0.00053  dbSNP: rs370077023

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000725232	SCV000237903	likely benign	not provided	2021-06-04	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000725232	SCV000335185	uncertain significance	not provided	2018-09-11	criteria provided, single submitter	clinical testing
Invitae	RCV000544778	SCV000642524	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-11-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844076	SCV002104070	likely benign	not specified	2022-02-07	criteria provided, single submitter	clinical testing	Variant summary: TTN c.94953T>A (p.Ser31651Arg) results in a non-conservative amino acid change located in the M-band region of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 248982 control chromosomes, predominantly at a frequency of 0.0017 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 4 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.94953T>A in individuals affected with Dilated Cardiomyopathy/Limb Girdle Muscular Dystrophy or other TTN-related disorders and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely Benign, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002390482	SCV002674041	likely benign	Cardiovascular phenotype	2020-06-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Revvity Omics, Revvity	RCV000725232	SCV003825599	uncertain significance	not provided	2023-08-30	criteria provided, single submitter	clinical testing