7-117531001-G-A
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000492.4(CFTR):c.376G>A(p.Gly126Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,062 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. G126D) has been classified as Pathogenic.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.376G>A | p.Gly126Ser | missense_variant | Exon 4 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250896Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135580
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460062Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6AN XY: 726414
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:1Uncertain:1Other:1
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 01, 2021 | This sequence change replaces glycine with serine at codon 126 of the CFTR protein (p.Gly126Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs397508606, ExAC 0.01%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 19181743, 25042876). This variant is also known as c.508G>A. ClinVar contains an entry for this variant (Variation ID: 53808). 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 C0"). Experimental studies have shown that this missense change does not substantially affect CFTR function (PMID: 25042876). This variant disrupts the p.Gly126 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8163293, 10439967, 23974870, 27214204). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 21, 2025 | Variant summary: CFTR c.376G>A (p.Gly126Ser) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 250896 control chromosomes (gnomAD). c c.376G>A has been reported in the literature in at least one heterozygous individual affected with congenital bilateral absence of vas deferens (CBAVD), repeated respiratory infections and raised sweat chloride levels without a clinical diagnosis of cystic fibrosis (Sharma_2009). This report, however, does not provide unequivocal conclusions about association of the variant with cystic fibrosis. An experimental study measuring channel function by iodide efflux of the mutant protein compared to WT found to have normal protein maturation process and channel activity (Sharma _2015). However, a recent study conducted by Bihler et al reports approximately 25% of normal chloride channel conductance relative to wild type (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 19181743, 25042876, 38388235, 35913788). ClinVar contains an entry for this variant (Variation ID: 53808). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at