ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2813T>G (p.Val938Gly) (rs193922511)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029505 SCV000052156 pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 2019-05-30 criteria provided, single submitter clinical testing Variant summary: CFTR c.2813T>G (p.Val938Gly) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR036640) 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 1.6e-05 in 251512 control chromosomes, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.013). c.2813T>G has been reported in the literature in multiple individuals affected with Congenital Absence of the Vas Deferens (CBAVD and CUAVD), once in a homozygous state, and others in a compound heterozygous state with either 174delA (as stated in the paper), p.F508del or deletions of exons 22_23 (Dork_1997, Marcelli_2006, Robin_2007, Ratbi_2007). Because CBAVD/CUAVD is often found in patients with either one severe and one mild mutation or two mild mutations, the presence of this variant in CBAVD/CUAVD patients in trans with 174delA, p.F508del, or deletion of exons 22_23 suggests that the variant may be a "mild" mutation that contributes to disease. This variant has also been reported in patients screened for cystic fibrosis and idiopathic pancreatitis, however has not been identified in classic cases of cystic fibrosis (Sands_2015, Sofia_2016, De Wachter_2017). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and have classified the variant as having uncertain significance. Based on the evidence outlined above, this variant was classified as Pathogenic for CBAVD.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506921 SCV000601081 uncertain significance not specified 2017-03-16 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000730038 SCV000857746 uncertain significance not provided 2017-10-19 criteria provided, single submitter clinical testing
CFTR-France RCV001009382 SCV001169235 pathogenic Cystic fibrosis; CFTR-related disorders 2018-01-29 criteria provided, single submitter curation when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Ambry Genetics RCV001016664 SCV001177641 uncertain significance Inborn genetic diseases 2019-02-14 criteria provided, single submitter clinical testing The p.V938G variant (also known as c.2813T>G), located in coding exon 17 of the CFTR gene, results from a T to G substitution at nucleotide position 2813. The valine at codon 938 is replaced by glycine, an amino acid with dissimilar properties. This variant was identified in two individuals; one individual was homozygous and presented with congenital unilateral absence of the vas deferens (CUAVD) and asthma bronchiale. The other individual was heterozygous for this variant as well as a frameshift alteration and presented with congenital bilateral absence of the vas deferens (CBAVD) and a borderline sweat chloride level; the phase of these alterations was not provided (Dörk T et al. Hum. Genet. 1997 Sep; 100(3-4):365-77). In another study, this variant was observed in one individual with CBAVD and a gross deletion (Ratbi I et al. Hum. Reprod. 2007 May;22(5):1285-91). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this variant remains unclear.
Invitae RCV001378467 SCV001576038 likely pathogenic Cystic fibrosis 2020-09-16 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 938 of the CFTR protein (p.Val938Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs193922511, ExAC 0.006%). This variant has been observed in individual(s) with cystic fibrosis, unilateral congenital absence of the vas deferens, or bilateral absence of the vas deferens (PMID: 9272157, 17329263, 28603918). ClinVar contains an entry for this variant (Variation ID: 35850). 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: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C1). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 5

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