ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.902A>G (p.Tyr301Cys) (rs150691494)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000590275 SCV000232563 uncertain significance not provided 2018-06-15 criteria provided, single submitter clinical testing
GeneDx RCV000590275 SCV000568549 uncertain significance not provided 2017-01-24 criteria provided, single submitter clinical testing The Y301C variant in the CFTR gene has been reported previously in individuals with an additional variant in CFTR who screened positive for cystic fibrosis on newborn screening; however, these individuals had inconclusive diagnosis with normal sweat chloride levels at followup (Castellani et al., 1999; Ooi et al., 2015). The Y301C variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y301C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R297W, A299T) have been reported in the Human Gene Mutation Database in association with CFTR-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret Y301C as a variant of uncertain significance.
Invitae RCV000525077 SCV000625755 uncertain significance Cystic fibrosis 2018-05-11 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 301 of the CFTR protein (p.Tyr301Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs150691494, ExAC 0.07%). This variant has been reported as heterozygous in individuals affected with cystic fibrosis (PMID: 23276700), lung caner (PMID: 9921909), asthma (PMID: 11354633), hypertrypsinaemia (PMID: 11303517). In addition, it was reported in one individual who was homozygous for the 7T allele in intron 9 and is affected with cystic fibrosis (PMID: 28040058). ClinVar contains an entry for this variant (Variation ID: 198738). 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: "Deleterious"; PolyPhen-2: "Benign"; 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 RCV000590275 SCV000697054 uncertain significance not provided 2017-01-27 criteria provided, single submitter clinical testing Variant summary: The c.902A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 5/5 in-silico tools predict damaging outcome for this variant. This variant is found in 46/120980 control chromosomes at a frequency of 0.0003802, which does not exceed the maximal expected frequency of a pathogenic allele in CFTR gene (0.0129603). Variant has been reported in several individuals in either heterozygous or compound heterozygous state. Among them, one prenatal case, two neonatal cases, and one adult case were shown to be compound heterozygotes for this variant and F508del or c.948delT (both classified as pathogenic) (Poulou_JCF_2014; Castellani_AJHG_1999; Schwartz_JMD_2009). None of these cases had elevated sweat chloride levels, and it is unclear if they have CF-related phenotypes such as CBAVD or were PI. One clinical laboratory classified this variant as VUS without evidence to independently evaluate. Because of the lack of clinical information and functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.

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