rs193922511
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000492.4(CFTR):āc.2813T>Gā(p.Val938Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V938L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.2813T>G | p.Val938Gly | missense_variant | 17/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.2813T>G | p.Val938Gly | missense_variant | 17/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152240Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251412Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135868
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461758Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727178
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152240Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74372
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 10, 2024 | 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 highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 938 of the CFTR protein (p.Val938Gly). This variant is present in population databases (rs193922511, gnomAD 0.003%). This missense change has been observed in individuals 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFTR protein function with a negative predictive value of 80%. This variant disrupts the p.Val938 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 9272157, 17329263, 28603918, 32777524, 36437957), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
CFTR-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 18, 2021 | - - |
Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 06, 2023 | 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 (IPR011527) 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 (gnomAD), which does not exceed the estimated maximal expected allele frequency for a pathogenic CFTR variant causing CF/CFTR-RD/CBAVD. c.2813T>G has been reported in the literature in multiple individuals affected with Congenital Absence of the Vas Deferens (CBAVD and CUAVD)/infertility, once in a homozygous state, and others in a compound heterozygous state with other pathogenic CFTR variants (e.g., Dork_1997, Marcelli_2006, Robin_2007, Ratbi_2007, Rudnik-Schoneborn_2021). Because CBAVD/CUAVD is often found in patients with either one severe and one mildly pathogenic variant or two mildly pathogenic variants, the presence of this variant in CBAVD/CUAVD patients in trans with severe variants suggests that the variant may be a "mild" variant that contributes to CFTR-related disease. This variant has also been reported in patients screened for cystic fibrosis, idiopathic pancreatitis and other CFTR-related diseases, however not in well phenotyped cases of classic cystic fibrosis associated with pancreatic/pulmonary insufficiency (e.g., Sands_2015, Sofia_2016, De Wachter_2017, Bozdogan_2021, Nykamp_2021). At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in approximately 35% of normal chloride channel conductance relative to wild type (e.g., Bihler_2023 (bioRxiv, no PMID)). The following publications have been ascertained in the context of this evaluation (PMID: 33572515, 28830496, 18685558, 20059485, 9272157, 17175965, 34196078, 17329263, 17507277, 33374015, 26003066, 31674704, 27264265, 10755189, 26277102). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS, n = 3; likely pathogenic, n = 1; pathogenic, n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 16, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 19, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at