rs397508598
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000492.4(CFTR):c.3719T>G(p.Val1240Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1240L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense, splice_region
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.3719T>G | p.Val1240Gly | missense_variant, splice_region_variant | 23/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3719T>G | p.Val1240Gly | missense_variant, splice_region_variant | 23/27 | 1 | NM_000492.4 | P2 | |
ENST00000456270.1 | n.65+4912A>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250942Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135608
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461124Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726898
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:4Uncertain:1Other:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 10, 2022 | This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1240 of the CFTR protein (p.Val1240Gly). This variant is present in population databases (rs397508598, gnomAD 0.0009%). This missense change has been observed in individuals with cystic fibrosis (PMID: 20059485, 22892530, 23974870; Invitae). ClinVar contains an entry for this variant (Variation ID: 53795). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 04, 2023 | Variant summary: CFTR c.3719T>G (p.Val1240Gly) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain 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 250942 control chromosomes. c.3719T>G has been reported in the literature in individuals affected with Cystic Fibrosis in some cases without second allele reported (Dorfman_2008, Lucarelli_2015) and in some cases reported along with known pathogenic variants (Sobczynska-Tomaszewska_2013, McCague_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The variant is reported to be FDA-approved for treatment with ivacaftor + tezacaftor + elexacaftor and ivacaftor + tezacaftor (Raraigh_2022). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One submitter classified the variant as VUS while three classified the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | curation | Institute of Human Genetics, University of Leipzig Medical Center | Sep 05, 2022 | This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM2_SUP, PM3_STR, PP3 - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Aug 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at