Submissions for variant NM_000492.4(CFTR):c.2026C>G (p.Pro676Ala)

dbSNP: rs762888022

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001242641	SCV001174779	likely benign	Cystic fibrosis	2019-07-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV001242641	SCV001415743	uncertain significance	Cystic fibrosis	2022-07-10	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 676 of the CFTR protein (p.Pro676Ala). This variant is present in population databases (rs762888022, gnomAD 0.02%). 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: 820539). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Genome-Nilou Lab	RCV001242641	SCV001822094	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003396600	SCV004110629	uncertain significance	CFTR-related condition	2023-02-06	criteria provided, single submitter	clinical testing	The CFTR c.2026C>G variant is predicted to result in the amino acid substitution p.Pro676Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.022% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117232247-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.