Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001192400 | SCV001360487 | likely pathogenic | Congenital bilateral aplasia of vas deferens from CFTR mutation | 2024-08-09 | criteria provided, single submitter | clinical testing | Variant summary: CFTR c.1397C>T (p.Ser466Leu) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of 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 251204 control chromosomes. c.1397C>T has been reported in at least two compound heterozygous individuals affected with Congenital Bilateral Absence of the Vas Deferens (CBAVD), where both of these patients also carried a well-known CFTR disease variant (Steiner_2011 and in the SickKids database). At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating that the variant protein in Xenopus oocytes has a significantly decreased Cl- channel function, with a residual whole cell Cl- conductance of about 8-10% of the wild type (Boucherot_2001). The following publications have been ascertained in the context of this evaluation (PMID: 11597353, 11504857, 35913788, 20021716, 25880441, 29497617, 25735457, 21520337, 26277102). ClinVar contains an entry for this variant (Variation ID: 53245). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Ambry Genetics | RCV002390195 | SCV002697683 | likely pathogenic | Cystic fibrosis | 2023-08-09 | criteria provided, single submitter | clinical testing | The p.S466L variant (also known as c.1397C>T), located in coding exon 11 of the CFTR gene, results from a C to T substitution at nucleotide position 1397. The serine at codon 466 is replaced by leucine, an amino acid with dissimilar properties. This variant was identified in one azoospermic male; however, complete genotype information was not provided (Gallati S et al. Reprod. Biomed. Online, 2009 Nov;19:685-94). It was also detected in conjunction with a nonsense alteration in a male with congenital absence of the vas deferencs (CBAVD) (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). In addition, this variant demonstrated reduced chloride function when expressed in Xenopus oocytes (Boucherot A et al. Biochim. Biophys. Acta, 2001 Nov;1515:64-71). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Fulgent Genetics, |
RCV002496708 | SCV002807599 | likely pathogenic | Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation | 2022-04-29 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV002390195 | SCV003271454 | uncertain significance | Cystic fibrosis | 2022-08-05 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 466 of the CFTR protein (p.Ser466Leu). This variant is present in population databases (rs121908805, gnomAD 0.0009%). This missense change has been observed in individuals with congenital absence of the vas deferens (PMID: 20021716, 21520337, 26277102). ClinVar contains an entry for this variant (Variation ID: 53245). 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 C0"). Experimental studies have shown that this missense change affects CFTR function (PMID: 11597353). 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. |
| Baylor Genetics | RCV003473453 | SCV004213365 | likely pathogenic | Bronchiectasis with or without elevated sweat chloride 1 | 2023-09-21 | criteria provided, single submitter | clinical testing |