Submissions for variant NM_000492.4(CFTR):c.166G>A (p.Glu56Lys)

gnomAD frequency: 0.00001  dbSNP: rs397508256

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000046399	SCV000245908	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
PharmGKB	RCV000660826	SCV000783065	drug response	ivacaftor response - Efficacy	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046399	SCV000696860	likely pathogenic	Cystic fibrosis	2016-02-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004228	SCV001163104	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV001009396	SCV001169249	pathogenic	Cystic fibrosis; CFTR-related disorder	2018-03-09	criteria provided, single submitter	curation	when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Invitae	RCV000046399	SCV001582754	pathogenic	Cystic fibrosis	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 56 of the CFTR protein (p.Glu56Lys). This variant is present in population databases (rs397508256, gnomAD 0.003%). This missense change has been observed in individual(s) with CFTR-related disorders (PMID: 9272157, 24816901, 26651825). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53325). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399, 23924900). This variant disrupts the p.Glu56 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 25910067), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000046399	SCV002704422	likely pathogenic	Cystic fibrosis	2022-04-28	criteria provided, single submitter	clinical testing	The p.E56K variant (also known as c.166G>A), located in coding exon 3 of the CFTR gene, results from a G to A substitution at nucleotide position 166. The glutamic acid at codon 56 is replaced by lysine, an amino acid with similar properties. This alteration has been observed once in a cohort of men with congenital absense of the vas deferens. The patient also had deltaF508 in trans with this variant and upon further evaluation also presented with elevated sweat chloride levels and recurrent lung infections (Dork T et al. Hum Genet.1997;100(3-4):365-377). Functional studies also determined that the effect of this variant on the CFTR protein was deleterious. Five individuals with cystic fibrosis were reported with this variant, but the second pathogenic mutation and clinical information on these patients was not available (The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org. Accessed March 25, 2014 and Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). This amino acid position is completely conserved on sequence alignment. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Baylor Genetics	RCV003473461	SCV004213485	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-11-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003480043	SCV004226564	pathogenic	not provided	2022-10-26	criteria provided, single submitter	clinical testing	PP5, PM2, PM3, PS3
Counsyl	RCV000046399	SCV000794273	likely pathogenic	Cystic fibrosis	2017-10-06	no assertion criteria provided	clinical testing