ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.365A>G (p.Tyr122Cys) (rs377295859)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000471538 SCV000552134 uncertain significance Cystic fibrosis 2019-07-24 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 122 of the CFTR protein (p.Tyr122Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs377295859, ExAC 0.002%). This variant has been observed as homozygous in an individual affected with chronic pancreatitis (PMID: 19812525). ClinVar contains an entry for this variant (Variation ID: 411120). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Integrated Genetics/Laboratory Corporation of America RCV000586920 SCV000696980 uncertain significance not provided 2016-01-21 criteria provided, single submitter clinical testing Variant summary: CFTR c.365A>G affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 5/5 in-silico tools predict damaging outcome for this variant, however these predictions have not been verified with functional studies. This variant is found in 1/120558 control chromosomes at a frequency of 0.0000083, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0129603). The variant has been cited in 1 homozygous individual with alcoholic etiology of chronic pancreatitis (ACP) without evidence of causation (ie co-segregation). Because of the absence of significant clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001893 SCV001159637 uncertain significance not specified 2018-12-09 criteria provided, single submitter clinical testing The CFTR variant, c.365A>G; p.Tyr122Cys, has been described individuals suspected to have mild cystic fibrosis (CF) (de Cid 2010, SickKids database). This variant is reported as uncertain significance in ClinVar (Variation ID: 411120), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The tyrosine at codon 122 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, a different variant at this residue, c.364T>C; p.Tyr122His, has been described in an individual affected with congenital bilateral absence of the vas deferens (CBAVD) (Radpour 2006). Due to limited information, the clinical significance of the p.Tyr122Cys variant is uncertain at this time. References: Link to SickKids database for Tyr122Cys: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=1624 de Cid R et al.Independent contribution of common CFTR variants to chronic pancreatitis. Pancreas. 2010 Mar;39(2):209-15. Radpour R et al. Two novel missense and one novel nonsense CFTR mutations in Iranian males with congenital bilateral absence of the vas deferens. Mol Hum Reprod. 2006 12(11):717-21.

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