Submissions for variant NM_001267550.2(TTN):c.8938G>A (p.Ala2980Thr)

gnomAD frequency: 0.00134  dbSNP: rs72647885

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000082457	SCV000051504	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040847	SCV000064538	likely benign	not specified	2016-01-26	criteria provided, single submitter	clinical testing	p.Ala2980Thr in exon 38 of TTN: This variant is not expected to have clinical si gnificance because it is not located within the splice consensus sequence and ha s been identified in 0.3% (35/10390) of African chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs72647885).
Eurofins Ntd Llc (ga)	RCV000040847	SCV000114486	likely benign	not specified	2015-08-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000040847	SCV000238051	likely benign	not specified	2017-03-08	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.
Invitae	RCV001084542	SCV000555604	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-24	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000040847	SCV000616170	benign	not specified	2017-02-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000082457	SCV001153166	likely benign	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001133640	SCV001293349	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-28	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	RCV001133641	SCV001293350	benign	Tibial muscular dystrophy	2017-09-24	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001133642	SCV001293351	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-09-24	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001133643	SCV001293352	uncertain significance	Dilated cardiomyopathy 1G	2017-04-28	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	RCV001133644	SCV001293353	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2017-04-28	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040847	SCV001448484	likely benign	not specified	2020-11-16	criteria provided, single submitter	clinical testing	Variant summary: TTN c.8938G>A (p.Ala2980Thr) results in a non-conservative amino acid change located in the I-band 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 0.00037 in 250936 control chromosomes, predominantly at a frequency of 0.0037 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 9 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. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign n=7, VUS n=1). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000082457	SCV001474053	likely benign	not provided	2020-08-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444495	SCV002682667	likely benign	Cardiovascular phenotype	2018-12-05	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	RCV003486612	SCV004240181	benign	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004534948	SCV004753568	likely benign	TTN-related disorder	2020-02-28	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	RCV000082457	SCV001921696	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000082457	SCV001970089	likely benign	not provided		no assertion criteria provided	clinical testing