Submissions for variant NM_000492.4(CFTR):c.228T>G (p.Cys76Trp)

dbSNP: rs777536750

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001050257	SCV001175877	uncertain significance	Cystic fibrosis	2019-09-11	criteria provided, single submitter	clinical testing	The p.C76W variant (also known as c.228T>G), located in coding exon 3 of the CFTR gene, results from a T to G substitution at nucleotide position 228. The cysteine at codon 76 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant has been detected with p.F508del in an individual with azoospermia, and an individual from a cystic fibrosis (CF) registry including patients with CF-related features; however, details were limited, and the phase of the alterations was not specified (Nick JA et al. Am. J. Respir. Crit. Care Med., 2010 Sep;182:614-26; Oud MS et al. Hum. Mutat., 2017 11;38:1592-1605). This variant has also been detected in a control cohort (Schneider A et al. Gastroenterology, 2011 Jan;140:162-71). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001050257	SCV001214356	uncertain significance	Cystic fibrosis	2021-08-26	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with tryptophan at codon 76 of the CFTR protein (p.Cys76Trp). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is present in population databases (rs777536750, ExAC 0.001%). This missense change has been observed in individual(s) with congenital absence of the vas deferens (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Genome-Nilou Lab	RCV001050257	SCV002027334	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331022	SCV004039517	uncertain significance	not specified	2023-08-02	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.228T>G (p.Cys76Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251012 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.228T>G has been reported in the literature in individuals affected with Cystic Fibrosis, CBAVD, or azoospermia with other pathogenic variants in an unknown phase (Nick_2010, Oud_2017, Steiner_2011). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20448091, 28801929, 21520337). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001827189	SCV002080091	uncertain significance	CFTR-related disorders	2018-09-28	no assertion criteria provided	clinical testing