Submissions for variant NM_001267550.2(TTN):c.30181A>C (p.Lys10061Gln)

gnomAD frequency: 0.00048  dbSNP: rs184153985

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040099	SCV000063790	uncertain significance	not specified	2013-06-27	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Lys8817Gln vari ant in TTN has been identified by our laboratory in 1 Black individual with isol ated right atrial enlargement and 1 Black individual with HCM (LMM unpublished d ata). It has also been identified in 1.1% (2/176) of Yoruba chromosomes by the 1 000 Genomes Project (dbSNP rs184153985) and 3/3884 African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Lysin e (Lys) at position 8817 is not completely conserved and 2 fish (tetradon and fu gu) carry a glutamine (Gln; this variant) at this position, raising the possibil ity that this change may be tolerated. Other computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong su pport for or against an impact to the protein. Although the frequency of this va riant suggests that it may be more likely benign, additional studies are needed to fully assess its clinical significance.
GeneDx	RCV001703899	SCV000237052	likely benign	not provided	2020-03-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468986	SCV000555118	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2025-01-20	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768894	SCV000900267	benign	Cardiomyopathy	2019-09-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040099	SCV002547642	benign	not specified	2022-05-09	criteria provided, single submitter	clinical testing	Variant summary: TTN c.26449A>C (p.Lys8817Gln) results in a conservative amino acid change located in the I-band of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 249222 control chromosomes, predominantly at a frequency of 0.0016 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 4 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.26449A>C in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Revvity Omics, Revvity	RCV001703899	SCV003825426	uncertain significance	not provided	2019-12-02	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000040099	SCV005621898	likely benign	not specified	2024-10-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541142	SCV004780915	uncertain significance	TTN-related disorder	2023-10-27	no assertion criteria provided	clinical testing	The TTN c.30181A>C variant is predicted to result in the amino acid substitution p.Lys10061Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.17% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179568916-T-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.