Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins Ntd Llc |
RCV000373122 | SCV000344798 | uncertain significance | not provided | 2016-08-12 | criteria provided, single submitter | clinical testing | |
Mendelics | RCV000757859 | SCV000886371 | uncertain significance | Cystic fibrosis | 2018-11-05 | criteria provided, single submitter | clinical testing | |
Johns Hopkins Genomics, |
RCV000757859 | SCV001762363 | uncertain significance | Cystic fibrosis | 2021-07-07 | criteria provided, single submitter | clinical testing | CFTR c.1499G>A has been identified in 2 individuals with features of cystic fibrosis. This CFTR variant (rs774945680) is rare (<0.1%) in a large population dataset (gnomAD: 2/251288 total alleles; 0.0008%; no homozygotes) and has been reported in ClinVar (Variation ID: 290277). Three bioinformatic tools queried predict that this substitution would be damaging and the glycine residue at this position is evolutionarily conserved across all species assessed. We consider the clinical significance of CFTR c.1499G>A to be uncertain at this time. |
Genome- |
RCV000757859 | SCV002027413 | uncertain significance | Cystic fibrosis | 2021-09-05 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000757859 | SCV002303349 | uncertain significance | Cystic fibrosis | 2022-09-18 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 500 of the CFTR protein (p.Gly500Asp). This variant is present in population databases (rs774945680, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 290277). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFTR protein function. 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV002222480 | SCV002500257 | uncertain significance | not specified | 2022-03-09 | criteria provided, single submitter | clinical testing | Variant summary: CFTR c.1499G>A (p.Gly500Asp) 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 8e-06 in 251288 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, listed as p.G500D but with a potential typo in the c.name, was reported in a CF patient with Aspergillus infection (Sabino_2015). To our knowledge, no experimental evidence demonstrating the variants impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
Ambry Genetics | RCV000757859 | SCV002701322 | pathogenic | Cystic fibrosis | 2020-08-31 | criteria provided, single submitter | clinical testing | The p.G500D pathogenic mutation (also known as c.1499G>A), located in coding exon 11 of the CFTR gene, results from a G to A substitution at nucleotide position 1499. The glycine at codon 500 is replaced by aspartic acid, an amino acid with similar properties. In our internal cohort, this alteration was identified in trans with p.F508del mutation in an individual with cystic fibrosis (CF) (Ambry internal data). This mutation was also reported in conjugation with p.G542* in another individual with CF; however, the phase was not provided (Sabino R et al. J. Cyst. Fibros., 2015 Jul;14:474-81). In addition, internal structural analysis revealed that this alteration is more destabilizing than known pathogenic variants within the same domain (Flachowsky S et al. Zentralbl Gynakol, 1986;108:383-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |