rs201686600
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_000492.4(CFTR):c.4045G>A(p.Gly1349Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,020 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1349D) has been classified as Pathogenic.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.4045G>A | p.Gly1349Ser | missense_variant | 25/27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.4045G>A | p.Gly1349Ser | missense_variant | 25/27 | 1 | NM_000492.4 | ENSP00000003084.6 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251176Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135746
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461726Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727184
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152294Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74468
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 03, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1349 of the CFTR protein (p.Gly1349Ser). This variant is present in population databases (rs201686600, gnomAD 0.02%). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 15463840). ClinVar contains an entry for this variant (Variation ID: 53880). 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. Experimental studies have shown that this missense change affects CFTR function (PMID: 7694298, 8741733). This variant disrupts the p.Gly1349 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7544319, 10200050, 23974870, 26911355). 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 21, 2022 | The p.G1349S variant (also known as c.4045G>A), located in coding exon 25 of the CFTR gene, results from a G to A substitution at nucleotide position 4045. The glycine at codon 1349 is replaced by serine, an amino acid with similar properties. A patch-clamp assay showed that the G1349S alteration slowed the rate of steady-state activation (Wilkinson DJ et al. J Gen Physiol, 1996 Jan;107:103-19). This alteration has been detected in individuals with CFTR-related disorders, including chronic pancreatitis and congenital absence of the vas deferens (CAVD) (Nakano E et al. Dig Dis Sci, 2015 May;60:1297-307; Sakamoto H et al. Int J Urol, 2008 Mar;15:270-1; Anzai C et al. J Cyst Fibros, 2003 Mar;2:14-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 21, 2024 | Variant summary: CFTR c.4045G>A (p.Gly1349Ser) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) 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 251282 control chromosomes. c.4045G>A has been reported in the literature in individuals affected with Congenital Bilateral Absence Of The Vas Deferens, pancreatitis, and neonatal cholestasis (Anzai_2003, Nakano_2015, Yin_2022, Ito_2022). These data do not allow any conclusion about variant significance. A different variant affecting the same codon has been classified as pathogenic by our lab (c.4046G>A, p.Gly1349Asp), supporting the critical relevance of codon 1349 to CFTR protein function. At least one publication reports experimental evidence that this variant slowed the rate of approach to steady state activation (Smit_1993, Wilkinson_1996). This variant is also known as c.4177G>A. The following publications have been ascertained in the context of this evaluation (PMID: 15463840, 8741733, 25735457, 25492507, 7694298, 37168916, 35171259). ClinVar contains an entry for this variant (Variation ID: 53880). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 27, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at