Submissions for variant NM_001267550.2(TTN):c.4671G>A (p.Met1557Ile)

gnomAD frequency: 0.00097  dbSNP: rs139192633

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152504	SCV000201674	likely benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	Met1557Ile in exon 27 of TTN: This variant is not expected to have clinical sign ificance because it has been identified in 0.3% (12/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs139192633).
GeneDx	RCV001704105	SCV000238001	likely benign	not provided	2021-02-12	criteria provided, single submitter	clinical testing
Invitae	RCV000232506	SCV000286680	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000152504	SCV000616090	benign	not specified	2017-01-24	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000152504	SCV000701503	likely benign	not specified	2016-09-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621269	SCV000736564	likely benign	Cardiovascular phenotype	2018-10-23	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001704105	SCV001471556	uncertain significance	not provided	2019-08-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000152504	SCV004100190	likely benign	not specified	2023-09-26	criteria provided, single submitter	clinical testing	Variant summary: TTN c.4671G>A (p.Met1557Ile) results in a conservative amino acid change located near the Z-disc domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 250408 control chromosomes, predominantly at a frequency of 0.0035 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 9-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.4671G>A has been reported in the literature in a sudden infant death case with other co-occurring variants (Campuzano_2018). This report does 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. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as benign/likely benign (n=5) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004544382	SCV004759579	likely benign	TTN-related disorder	2021-12-15	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).