Submissions for variant NM_001267550.2(TTN):c.55673G>A (p.Arg18558His)

gnomAD frequency: 0.00016  dbSNP: rs115867512

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152297	SCV000201162	likely benign	not specified	2020-09-22	criteria provided, single submitter	clinical testing	The p.Arg15990His variant in TTN is classified as likely benign because it has been identified in 0.02% (6/24148) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. ACMG/AMP Criteria applied: BS1.
Invitae	RCV000226098	SCV000286724	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2016-12-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000835240	SCV000977027	likely benign	not provided	2018-04-05	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.
CeGaT Center for Human Genetics Tuebingen	RCV000835240	SCV001152867	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000835240	SCV001714647	uncertain significance	not provided	2019-06-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433659	SCV002748140	likely benign	Cardiovascular phenotype	2020-07-21	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	RCV000835240	SCV003819813	uncertain significance	not provided	2022-11-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000152297	SCV004121830	uncertain significance	not specified	2023-10-02	criteria provided, single submitter	clinical testing	Variant summary: TTN c.47969G>A (p.Arg15990His) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 245456 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (7.7e-05 vs 0.00039), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.47969G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=4) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.