Submissions for variant NM_001267550.2(TTN):c.64654A>G (p.Ile21552Val)

gnomAD frequency: 0.00036  dbSNP: rs201247592

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001704914	SCV000237418	likely benign	not provided	2020-01-16	criteria provided, single submitter	clinical testing
Invitae	RCV000465010	SCV000555487	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000184718	SCV001572367	benign	not specified	2023-11-28	criteria provided, single submitter	clinical testing	Variant summary: TTN c.56950A>G (p.Ile18984Val) 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 5.1e-05 in 1,598,426 control chromosomes, predominantly at a frequency of 0.001 within the African or African-American subpopulation in the gnomAD database (v4.0 dataset). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.5-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. c.56950A>G has been reported in the literature in an individual affected with Arrhythmogenic Right Ventricular Cardiomyopathy (Campuzano_2015), however in a later study, authors re-classified this variant as benign (Martinez-Barrios_2022). In addition, the variant was also reported in a family affected with Limb-Girdle Muscular dystrophy, where a co-occurring homozygous pathogenic variant in the SGCA gene could explain the phenotype (Dardas_2020). These reports do not support the association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26516846, 31953240, 35207729). Three other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002362953	SCV002625728	likely benign	Cardiovascular phenotype	2019-10-22	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.