rs397508784
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000492.4(CFTR):āc.709C>Gā(p.Gln237Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,994 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q237H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.709C>G | p.Gln237Glu | missense_variant | 6/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.709C>G | p.Gln237Glu | missense_variant | 6/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251392Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135862
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461860Hom.: 1 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 727236
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74302
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:1Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 10, 2023 | Variant summary: CFTR c.709C>G (p.Gln237Glu) results in a conservative amino acid change located in the transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251392 control chromosomes (gnomAD). c.709C>G has been reported in the literature and in multiple databases in individuals affected with Cystic Fibrosis, including multiple examples where it was found in the compound heterozygous state together with a pathogenic variant (e.g. Claustres_2000, Hubert_2004, Giardet_2007, Gaitch_2016, DeWachter_2017, Ramalho_2021, Vaidyanathan_2022); however, in two of these cases, the individual either was asymptomatic or had a mild phenotype/late disease onset (e.g. Ramhalo_2021, Mekki_2021), suggesting this variant may have varying clinical consequences. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating forskolin induced swelling (FIS) of organoids from a CF patient with the genotype F508del/Q237E, and found there was some residual CFTR function that improved with treatment with ivacaftor, however, as the variant was not examined in isolation, it does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 10923036, 28830496, 27086061, 17850636, 15463882, 33946859, 32747394, 35857025). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Cystic fibrosis;na:CFTR-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Sep 02, 2020 | when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at