Submissions for variant NM_001267550.2(TTN):c.96098G>A (p.Arg32033His)

gnomAD frequency: 0.00090  dbSNP: rs200648462

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040831	SCV000064522	likely benign	not specified	2012-04-18	criteria provided, single submitter	clinical testing	Arg29465His in Exon 295 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (14/3210) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS;). Arg29465His in Exon 295 of TTN (allele frequency = 0.4%, 14/3210) **
GeneDx	RCV001703912	SCV000237817	likely benign	not provided	2021-09-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24503780)
Ambry Genetics	RCV000252794	SCV000319160	uncertain significance	Cardiovascular phenotype	2013-11-21	criteria provided, single submitter	clinical testing	The p.R29465H variant (also known as c.88394G>A) is located in coding exon 294 of the TTN gene. This alteration results from a G to A substitution at nucleotide position 88394. The arginine at codon 29465 is replaced by histidine, an amino acid with some highly similar properties. ​This variant was previously reported in the SNPDatabase as rs200648462. Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.14% (17/12,192), having been observed in 0.39% (15/3896) of African American alleles, and in 0.02% (2/8296) of European American alleles studied.This amino acid position is highly conserved on sequence alignment.This variant is predicted to be probably damaging by PolyPhen in silico analyses. Since supporting evidence is limited at this time, the clinical significance of p.R29465H remains unclear.
Eurofins Ntd Llc (ga)	RCV000040831	SCV000332160	likely benign	not specified	2015-06-11	criteria provided, single submitter	clinical testing
Invitae	RCV000463548	SCV000555332	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798201	SCV002043078	benign	Cardiomyopathy	2020-12-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040831	SCV002572092	likely benign	not specified	2022-08-16	criteria provided, single submitter	clinical testing	Variant summary: TTN c.88394G>A (p.Arg29465His) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 248528 control chromosomes, predominantly at a frequency of 0.0032 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 8-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. No penetrant association of c.88394G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=1)/likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV000252794	SCV003945343	likely benign	Cardiovascular phenotype	2023-05-25	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.
PreventionGenetics, part of Exact Sciences	RCV004534946	SCV004740334	likely benign	TTN-related disorder	2022-05-16	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).