Submissions for variant NM_001267550.2(TTN):c.83299C>A (p.Pro27767Thr)

gnomAD frequency: 0.00088  dbSNP: rs184643087

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040693	SCV000064384	uncertain significance	not specified	2014-03-19	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Pro25199Thr var iant in TTN has been detected in 0.2% (7/3804) of African American chromosomes b y the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP r s184643087). Computational prediction tools and conservation analysis suggest th at this variant may impact the protein, though this information is not predictiv e enough to determine pathogenicity. In summary, the frequency of this variant s uggests that it is more likely benign but is too low to confidently rule out a d isease-causing role. Additional information is needed to fully assess the clinic al significance of this variant.
GeneDx	RCV000040693	SCV000237645	likely benign	not specified	2017-11-30	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.
Eurofins Ntd Llc (ga)	RCV000725532	SCV000337568	uncertain significance	not provided	2017-04-18	criteria provided, single submitter	clinical testing
Invitae	RCV001087252	SCV000764751	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-20	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000040693	SCV001879711	benign	not specified	2021-01-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040693	SCV002041804	benign	not specified	2021-11-29	criteria provided, single submitter	clinical testing	Variant summary: TTN c.75595C>A (p.Pro25199Thr) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00076 in 150850 control chromosomes, predominantly at a frequency of 0.0027 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 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 African or African-American origin. To our knowledge, no occurrence of c.75595C>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign (n=1) / likely benign (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002345322	SCV002649212	likely benign	Cardiovascular phenotype	2019-06-26	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.
Revvity Omics, Revvity	RCV000725532	SCV003827949	uncertain significance	not provided	2023-09-25	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149659	SCV003838533	benign	Cardiomyopathy	2021-08-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003924974	SCV004744340	likely benign	TTN-related condition	2023-06-27	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).