Submissions for variant NM_000492.4(CFTR):c.1883G>C (p.Gly628Ala)

dbSNP: rs1554389290

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671291	SCV000796252	uncertain significance	Cystic fibrosis	2017-12-07	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000671291	SCV003839087	likely pathogenic	Cystic fibrosis	2022-12-27	criteria provided, single submitter	clinical testing	This CFTR variant has been reported in individuals with features of cystic fibrosis and has an entry in ClinVar (Variation ID: 555466)3. It is absent from a large population dataset. Two bioinformatic tools queried predict that this substitution would be damaging and the glycine residue at this position is evolutionarily conserved across all species assessed. A different missense variant (p.Gly628Arg) at this same position has been classified as a CF-causing variant. We consider CFTR c.1883G>C to be likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323672	SCV004028754	uncertain significance	not specified	2023-07-24	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1883G>C (p.Gly628Ala) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. This alters a highly conserved residue (HGMD) in which another missense change (p.Gly628Arg) is classified as pathogenic in ClinVar. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245128 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1883G>C has been reported in the literature in an individual diagnosed with Cystic Fibrosis (Kharrazi_2015). These data suggest the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26574590, 28471435). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000671291	SCV004354412	uncertain significance	Cystic fibrosis	2023-09-27	criteria provided, single submitter	clinical testing	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 expected to disrupt CFTR protein function. This variant disrupts the p.Gly628 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10923036, 20435887, 27022295). 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. ClinVar contains an entry for this variant (Variation ID: 555466). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 628 of the CFTR protein (p.Gly628Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 26574590).