Submissions for variant NM_001267550.2(TTN):c.289G>A (p.Val97Met)

gnomAD frequency: 0.00208  dbSNP: rs185921345

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155019	SCV000204702	likely benign	not specified	2014-04-10	criteria provided, single submitter	clinical testing	Val97Met in exon 3 of TTN: This variant is not expected to have clinical signifi cance because it has been identified in 2.2% (4/186) of Finnish chromosomes by t he 1000 Genomes Project (dbSNP rs185921345).
GeneDx	RCV000155019	SCV000238105	benign	not specified	2017-10-31	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.
Athena Diagnostics	RCV000155019	SCV000616047	benign	not specified	2017-01-24	criteria provided, single submitter	clinical testing
Invitae	RCV000529339	SCV000642939	benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840160	SCV002101674	benign	Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840161	SCV002101675	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840162	SCV002101676	benign	Early-onset myopathy with fatal cardiomyopathy	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840159	SCV002101677	benign	Tibial muscular dystrophy	2021-09-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433680	SCV002751820	likely benign	Cardiovascular phenotype	2020-03-26	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.
CeGaT Center for Human Genetics Tuebingen	RCV003884367	SCV004700597	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	TTN: BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155019	SCV004804016	benign	not specified	2024-01-30	criteria provided, single submitter	clinical testing	Variant summary: TTN c.289G>A (p.Val97Met) results in a conservative amino acid change located in the Z-disk region 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 0.0012 in 1614088 control chromosomes in the gnomAD database, including 18 homozygotes, and is found predominantly within individuals of Finnish ancestry at a frequency of 0.024. The observed variant frequency in the gnomAD database is approximately 3-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 benign. c.289G>A has been reported in the literature without evidence for causality in an individual affected with arrhythmogenic right ventricular cardiomyopathy and in an individual who suffered a sudden unexplained death and was found to have hypertrophic cardiomyopathy (Campuzano_2015, Sanchez_2016). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 178278). Based on the evidence outlined above, the variant was classified as benign.