Submissions for variant NM_001267550.2(TTN):c.74596A>G (p.Thr24866Ala)

gnomAD frequency: 0.00064  dbSNP: rs199784966

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000725164	SCV000237536	likely benign	not provided	2021-02-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29540445)
Eurofins Ntd Llc (ga)	RCV000725164	SCV000334582	uncertain significance	not provided	2015-09-14	criteria provided, single submitter	clinical testing
Invitae	RCV001082586	SCV000554989	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617309	SCV000735494	benign	Cardiovascular phenotype	2020-04-14	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265602	SCV002547647	likely benign	not specified	2022-05-02	criteria provided, single submitter	clinical testing	Variant summary: TTN c.66892A>G (p.Thr22298Ala) results in a non-conservative amino acid change located in the A-band 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 0.00015 in 247246 control chromosomes, predominantly at a frequency of 0.0022 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 6 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign n=3, VUS n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000725164	SCV003827340	uncertain significance	not provided	2020-12-10	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486643	SCV004240108	benign	Cardiomyopathy	2023-06-02	criteria provided, single submitter	clinical testing