Submissions for variant NM_001267550.2(TTN):c.74549A>G (p.Asp24850Gly)

gnomAD frequency: 0.00002  dbSNP: rs573415766

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000216300	SCV000272755	uncertain significance	not specified	2015-04-29	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Asp22282Gly v ariant in TTN has not been previously reported in individuals with cardiomyopath y, but has been identified in 0.25% (41/16430) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs573 415766). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while the c linical significance of the p.Asp22282Gly variant is uncertain, its frequency su ggests that it is more likely to be benign.
Eurofins Ntd Llc (ga)	RCV000725210	SCV000335014	uncertain significance	not provided	2015-09-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000328950	SCV000421819	uncertain significance	Myopathy, myofibrillar, 9, with early respiratory failure	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000376348	SCV000421820	uncertain significance	Hypertrophic cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000284422	SCV000421821	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000341722	SCV000421822	uncertain significance	Tibial muscular dystrophy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000396489	SCV000421823	uncertain significance	Dilated Cardiomyopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000278714	SCV000421824	uncertain significance	Limb-girdle muscular dystrophy, recessive	2016-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086254	SCV000555156	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-24	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000725210	SCV001146481	benign	not provided	2018-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000725210	SCV001823239	likely benign	not provided	2021-02-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000216300	SCV002104060	likely benign	not specified	2022-02-14	criteria provided, single submitter	clinical testing	Variant summary: TTN c.66845A>G (p.Asp22282Gly) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 247022 control chromosomes, predominantly at a frequency of 0.0026 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6.7 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 South Asian origin. To our knowledge, no occurrence of c.66845A>G in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=3; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004541343	SCV004788049	likely benign	TTN-related disorder	2022-06-13	no assertion criteria provided	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).