Submissions for variant NM_001267550.2(TTN):c.88297G>A (p.Asp29433Asn)

gnomAD frequency: 0.00153  dbSNP: rs189202799

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152196	SCV000200947	likely benign	not specified	2015-10-31	criteria provided, single submitter	clinical testing	Asp26865Asn in exon 279 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (45/9664) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs189202799).
GeneDx	RCV000152196	SCV000237695	likely benign	not specified	2017-10-10	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)	RCV000152196	SCV000336611	likely benign	not specified	2016-08-19	criteria provided, single submitter	clinical testing
Invitae	RCV001081700	SCV000555384	benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619720	SCV000736509	likely benign	Cardiovascular phenotype	2018-07-09	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.
Athena Diagnostics	RCV000714109	SCV000844782	benign	not provided	2018-07-20	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840080	SCV002102264	benign	Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840081	SCV002102265	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840082	SCV002102266	benign	Early-onset myopathy with fatal cardiomyopathy	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840079	SCV002102267	benign	Tibial muscular dystrophy	2021-09-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000152196	SCV004020362	benign	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: TTN c.80593G>A (p.Asp26865Asn) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 248128 control chromosomes, predominantly at a frequency of 0.0047 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 12-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.80593G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported in the literature. Additionally, a co-occurrence with another pathogenic variant has been observed (TTR c.424G>A, p.Val142Ile; internal data), providing supporting evidence for a benign role. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign (n=3)/likely benign (n=4). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004544365	SCV004774627	likely benign	TTN-related disorder	2020-11-10	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).