Submissions for variant NM_001267550.2(TTN):c.81671A>G (p.Asn27224Ser)

gnomAD frequency: 0.00012  dbSNP: rs368443217

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040671	SCV000064362	uncertain significance	not specified	2014-02-13	criteria provided, single submitter	clinical testing	The Asn24656Ser variant in TTN has not been reported in the literature. It has b een previously identified in one individual with HCM tested by our laboratory. This variant has been identified in 1/8194 European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington .edu/EVS/ ). The clinical features of that individual are uncertain. The affecte d amino acid is highly conserved in evolution suggesting that a change may not b e tolerated. Other computational analyses (biochemical amino acid properties, Al ignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an im pact to the protein. Additional information is needed to fully assess the clini cal significance of the Asn24656Ser variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000643828	SCV000765515	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-10-10	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727800	SCV000855212	uncertain significance	not provided	2018-07-11	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000727800	SCV001146508	uncertain significance	not provided	2019-02-21	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170785	SCV001333392	uncertain significance	Cardiomyopathy	2019-07-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000727800	SCV001805618	likely benign	not provided	2018-09-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345315	SCV002648107	likely benign	Cardiovascular phenotype	2020-06-12	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040671	SCV002766510	uncertain significance	not specified	2022-11-14	criteria provided, single submitter	clinical testing	Variant summary: TTN c.73967A>G (p.Asn24656Ser) results in a 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 8.2e-05 in 243932 control chromosomes. This frequency is not higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (8.2e-05 vs 0.00039), allowing no conclusion about variant significance. c.73967A>G has been reported in the literature in individuals affected with Cardiomyopathy (Campuzano_2015, Burstein_2021, Martinez-Barrios_2022). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with four classifying the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000727800	SCV003827951	uncertain significance	not provided	2022-05-12	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000727800	SCV001968894	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541180	SCV004763893	uncertain significance	TTN-related disorder	2024-01-08	no assertion criteria provided	clinical testing	The TTN c.81671A>G variant is predicted to result in the amino acid substitution p.Asn27224Ser. This variant has been reported in an individual with hypertrophic cardiomyopathy (Table S2, Burstein. 2020. PubMed ID: 32746448). This variant is reported in 0.018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.