Submissions for variant NM_001267550.2(TTN):c.61322A>G (p.Asn20441Ser)

gnomAD frequency: 0.00124  dbSNP: rs147580753

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040442	SCV000064133	likely benign	not specified	2013-02-22	criteria provided, single submitter	clinical testing	Asn17873Ser in exon 253 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (10/3832) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS/; dbSNP rs147580753) and in 1/176 chromosomes from a population of Yoruba individuals by the 1000 Genomes project (dbSNP rs147580753 ). Asn17873Ser in exon 253 of TTN (rs147580753; allele frequency = 0.3%, 10/38 32) **
Genetic Services Laboratory, University of Chicago	RCV000118772	SCV000153316	uncertain significance	not provided	2014-02-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000118772	SCV000237375	likely benign	not provided	2020-07-27	criteria provided, single submitter	clinical testing
Invitae	RCV001086533	SCV000286762	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-10	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000118772	SCV000701231	uncertain significance	not provided	2017-02-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617338	SCV000736496	likely benign	Cardiovascular phenotype	2018-08-02	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000118772	SCV001472513	likely benign	not provided	2023-11-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040442	SCV002547638	benign	not specified	2022-05-09	criteria provided, single submitter	clinical testing	Variant summary: TTN c.53618A>G (p.Asn17873Ser) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 273254 control chromosomes (gnomAD), predominantly at a frequency of 0.0037 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. 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. To our knowledge, no occurrence of c.53618A>G in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed the variant since 2014: two classify the variant as of uncertain significance and three as likely benign. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003914977	SCV004742630	likely benign	TTN-related condition	2020-03-10	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).