Submissions for variant NM_001267550.2(TTN):c.66650T>G (p.Phe22217Cys)

gnomAD frequency: 0.00003  dbSNP: rs764330098

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724201	SCV000228410	uncertain significance	not provided	2014-12-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000724201	SCV000237444	likely benign	not provided	2018-04-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705326	SCV000834317	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine with cysteine at codon 22217 of the TTN protein (p.Phe22217Cys). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is present in population databases (rs764330098, ExAC 0.002%). This variant has not been reported in the literature in individuals with TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 196004). Algorithms developed to predict the effect of missense changes on protein structure and function are unavailable for the TTN gene. This variant identified in the TTN gene is located in the A band of the resulting protein (PMID: 25589632). It is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002372089	SCV002624974	uncertain significance	Cardiovascular phenotype	2020-03-02	criteria provided, single submitter	clinical testing	The p.F13152C variant (also known as c.39455T>G), located in coding exon 143 of the TTN gene, results from a T to G substitution at nucleotide position 39455. The phenylalanine at codon 13152 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well 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	RCV000724201	SCV003819164	uncertain significance	not provided	2020-03-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537411	SCV004715127	uncertain significance	TTN-related disorder	2024-07-22	no assertion criteria provided	clinical testing	The TTN c.66650T>G variant is predicted to result in the amino acid substitution p.Phe22217Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0057% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.