Submissions for variant NM_001267550.2(TTN):c.6950G>A (p.Arg2317His)

gnomAD frequency: 0.00006  dbSNP: rs764882950

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000546592	SCV000643584	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-05-16	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770125	SCV000901551	uncertain significance	Cardiomyopathy	2016-01-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001567645	SCV001791369	likely benign	not provided	2019-01-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23910462)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824822	SCV002074504	likely benign	not specified	2022-01-31	criteria provided, single submitter	clinical testing	Variant summary: TTN c.6950G>A (p.Arg2317His) results in a non-conservative amino acid change located in the I-band region of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.3e-05 in 395656 control chromosomes, predominantly at a frequency of 0.00033 within the Latino subpopulation in the gnomAD database (in the v2.1 and v3.1 non-v2 datasets). This frequency is somewhat lower than the maximum expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00039). The variant c.6950G>A has been reported in the literature in at least two Spanish individuals with various disease phenotypes, including a 47-year-old individual, who died because of an unexplained cause, but was not found to be affected with Dilated Cardiomyopathy or by other structural cardiac alteration (Campuzano_2015, Sanchez_2016), and in a child affected with Jeune syndrome, who had apparently healthy parents (McInerney-Leo_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 likely benign (n=1) or VUS (n=). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002367862	SCV002665096	uncertain significance	Cardiovascular phenotype	2018-12-03	criteria provided, single submitter	clinical testing	The p.R2271H variant (also known as c.6812G>A), located in coding exon 28 of the TTN gene, results from a G to A substitution at nucleotide position 6812. The arginine at codon 2271 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV001567645	SCV003819717	uncertain significance	not provided	2020-08-12	criteria provided, single submitter	clinical testing