NM_000492.4:c.721G>A
Variant summary
Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong
The NM_000492.4(CFTR):c.721G>A(p.Gly241Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,982 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. G241W) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
Publications
- cystic fibrosisInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
- congenital bilateral absence of vas deferensInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- hereditary chronic pancreatitisInheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
Genome browser will be placed here
ACMG classification
Our verdict: Likely_pathogenic. The variant received 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.721G>A | p.Gly241Arg | missense_variant | Exon 6 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251394 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461858Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727228 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74306 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: CFTR c.721G>A (p.Gly241Arg) results in a non-conservative amino acid change located in the 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 4e-06 in 251394 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.721G>A has been reported in the literature in individuals affected with Cystic Fibrosis (e.g., Claustres_2000, LeMarechal_2001, Sasihuiseyinoglu_2019). These data indicate that the variant may be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g., Wehbi_2007). The following publications have been ascertained in the context of this evaluation (PMID: 11504857, 10923036, 11379874, 31990467, 17516627). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
not provided Uncertain:1
The CFTR c.721G>A; p.Gly241Arg variant (rs397508789, ClinVar variation ID: 54047) is reported in the literature in cystic fibrosis cohorts, however specifics were not provided (Le Marechal 2001, Claustres 2000) and in two infants with recurrent pneumonia suspected of cystic fibrosis who each had a second variant but the phase of the variants is unknown (Sasihuseyinoglu 2019). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.801). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-56. PMID: 10923036. Le Marechal C et al. Complete and rapid scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing high-performance liquid chromatography (D-HPLC): major implications for genetic counselling. Hum Genet. 2001 Apr;108(4):290-8. PMID: 11379874. Sasihuseyinoglu AS et al. Two years of newborn screening for cystic fibrosis in Turkey: Çukurova experience. Turk J Pediatr. 2019;61(4):505-512. PMID: 31990467. -
Cystic fibrosis Other:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at