Submissions for variant NM_001267550.2(TTN):c.95134T>C (p.Cys31712Arg)

dbSNP: rs869320740

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254991	SCV000322332	pathogenic	not provided	2020-10-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a that C30071R impairs solubility of the 119th fibronectin-3 domain, causing defective protein folding (Hedberg et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32039858, 27854229, 22577215, 24636144, 24444549, 29435569, 23514108, 25500009, 22577218, 30666435, 24980681, 24575448, 26518445, 26269091, 25253871, 32403337, 32307395)
Eurofins Ntd Llc (ga)	RCV000254991	SCV000338332	pathogenic	not provided	2016-01-08	criteria provided, single submitter	clinical testing
Invitae	RCV000627779	SCV000543100	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-08-04	criteria provided, single submitter	clinical testing	This variant is also known as g.274375T4C (p.Cys30071Arg). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 31712 of the TTN protein (p.Cys31712Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant hereditary myopathy with early respiratory failure (HMERF) (PMID: 24444549, 24980681, 25500009). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 132133). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects TTN function (PMID: 24636144). This variant is located in the A band of TTN (PMID: 25589632). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 23975875). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc	RCV000254991	SCV000616186	pathogenic	not provided	2017-07-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768851	SCV000900224	pathogenic	Cardiomyopathy	2017-05-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000254991	SCV002022465	pathogenic	not provided	2020-10-31	criteria provided, single submitter	clinical testing
3billion	RCV002250566	SCV002521009	pathogenic	Hypertrophic cardiomyopathy 9	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.80). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000132133) and a different missense change at the same codon (p.Cys31712Tyr) has been reported to be associated with TTN related disorder (PMID: 25253871). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 23514108, 24444549, 25500009). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen	RCV000254991	SCV002822726	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	TTN: PP1:Strong, PM1, PM2, PM5, PP4, PS4:Supporting
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000119021	SCV004047115	pathogenic	Myopathy, myofibrillar, 9, with early respiratory failure		criteria provided, single submitter	clinical testing	The TTN c.95134T>C variant has been reported in heterozygous state in individuals affected with Myopathy, myofibrillar, 9, with early respiratory failure (Chauveau et. al., 2014; Pfeffer et. al., 2014). It is a common cause of HMERF in individuals of many different ancestries (Pfeffer et. al., 2014, Yue et. al., 2015). Experimental studies have found that this missense change may interfere with the proper folding of the fibronectin III domain 119 of the TTN protein (Hedberg et. al., 2014). This variant has been reported to the ClinVar database as Pathogenic. The p.Cys31712Arg variant is novel (not in any individuals) in 1000 Genomes and has an allele frequency of 0.0004109% in gnomAD database. The amino acid Cys at position 31712 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
GeneReviews	RCV000119021	SCV000153723	not provided	Myopathy, myofibrillar, 9, with early respiratory failure		no assertion provided	literature only
OMIM	RCV000119021	SCV000897722	pathogenic	Myopathy, myofibrillar, 9, with early respiratory failure	2014-03-01	no assertion criteria provided	literature only