Submissions for variant NM_001267550.2(TTN):c.2686G>A (p.Val896Ile)

gnomAD frequency: 0.00029  dbSNP: rs376768790

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040109	SCV000063800	likely benign	not specified	2015-07-23	criteria provided, single submitter	clinical testing	p.Val896Ile in exon 16 of TTN: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, several mammals have isoleucine (Ile) at this position despite high nearby a mino acid conservation. This variant has been identified in 8/16510 South Asian chromosomes and 5/10404 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs376768790).
GeneDx	RCV000040109	SCV000237549	likely benign	not specified	2018-03-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Eurofins Ntd Llc (ga)	RCV000725605	SCV000338095	uncertain significance	not provided	2015-12-22	criteria provided, single submitter	clinical testing
Invitae	RCV000471292	SCV000542255	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2016-09-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620387	SCV000736824	likely benign	Cardiovascular phenotype	2019-03-19	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	RCV000770154	SCV000901580	uncertain significance	Cardiomyopathy	2015-10-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725605	SCV001248794	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	TTN: PM2, BP4
Illumina Laboratory Services, Illumina	RCV001135010	SCV001294775	uncertain significance	Dilated cardiomyopathy 1G	2017-04-27	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	RCV001135011	SCV001294776	likely benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-04-27	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001135012	SCV001294777	likely benign	Tibial muscular dystrophy	2017-04-27	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001135013	SCV001294778	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-27	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	RCV001135014	SCV001294779	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2017-04-27	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.
Revvity Omics, Revvity	RCV000725605	SCV003826731	uncertain significance	not provided	2023-10-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040109	SCV003934104	likely benign	not specified	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: TTN c.2686G>A (p.Val896Ile) results in a conservative amino acid change located near Z-disk 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 0.0002 in 251120 control chromosomes, predominantly at a frequency of 0.00056 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.4-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 South Asian origin. To our knowledge, no occurrence of c.2686G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Nine ClinVar submitters (evaluation after 2014) have reported the variant with conflicting assessments: 4 classify the variant as likely benign, and 5 classify the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004534885	SCV004113258	uncertain significance	TTN-related disorder	2023-02-20	criteria provided, single submitter	clinical testing	The TTN c.2686G>A variant is predicted to result in the amino acid substitution p.Val896Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.056% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179648886-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.