Submissions for variant NM_001267550.2(TTN):c.45499G>A (p.Val15167Ile)

gnomAD frequency: 0.00093  dbSNP: rs183245562

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040259	SCV000063950	likely benign	not specified	2013-02-25	criteria provided, single submitter	clinical testing	p.Val12599Ile in exon 195 of TTN: This variant is not expected to have clinical significance due to a lack of conservation across species. Multiple mammals hav e an isoleucine (Ile; this variant) at this position, despite high nearby amino acid conservation. Computational analyses (AlignGVGD, PolyPhen2, SIFT) do not su ggest a high likelihood of impact to the protein. This variant has also been ide ntified in 0.2% (8/3600) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs183245562).
GeneDx	RCV000725531	SCV000237190	likely benign	not provided	2020-06-10	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000725531	SCV000337564	uncertain significance	not provided	2015-11-12	criteria provided, single submitter	clinical testing
Invitae	RCV001084767	SCV000765408	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-20	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000040259	SCV001880265	benign	not specified	2021-01-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040259	SCV002041823	benign	not specified	2021-11-29	criteria provided, single submitter	clinical testing	Variant summary: TTN c.37795G>A (p.Val12599Ile) results in a conservative amino acid change located in the I-band region of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0008 in 150630 control chromosomes, predominantly at a frequency of 0.0029 within the African or African-American subpopulation in the gnomAD database (v3.1 genomes dataset). 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.37795G>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, and reported the variant as VUS (n=1), likely benign (n=2) / benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002408530	SCV002714646	likely benign	Cardiovascular phenotype	2019-06-26	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	RCV003149646	SCV003838619	benign	Cardiomyopathy	2021-08-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004534898	SCV004740054	likely benign	TTN-related disorder	2023-06-27	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	RCV000040259	SCV001919590	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000040259	SCV001959682	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000725531	SCV001967416	likely benign	not provided		no assertion criteria provided	clinical testing