Submissions for variant NM_000492.4(CFTR):c.1651G>A (p.Gly551Ser)

dbSNP: rs121909013

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007562	SCV000245884	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
PharmGKB	RCV000211256	SCV000268177	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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224595	SCV000281129	pathogenic	not provided	2015-05-26	criteria provided, single submitter	clinical testing
Counsyl	RCV000007562	SCV000485648	likely pathogenic	Cystic fibrosis	2016-01-20	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000007562	SCV001167249	pathogenic	Cystic fibrosis	2019-10-16	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007562	SCV001360489	pathogenic	Cystic fibrosis	2022-02-24	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1651G>A (p.Gly551Ser) results in a non-conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domains 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 250911 control chromosomes. c.1651G>A has been reported in the literature in multiple individuals affected with Cystic Fibrosis in the homozygous and compound heterozygous state (examples: Orozco_1995, Strong_1991, McCague_2019). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that although the variant was found to have no effect on bicarbonate permeability or chloride transport, it did result in a negative effect in a number of other CFTR functions including activation of chloride conductance, probability of channel opening and biocarbonate transport (Tang_2009, Choi_2001, Wilkinson_1996, Anderson_1992, Drumm_1991). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000007562	SCV001581779	pathogenic	Cystic fibrosis	2022-07-04	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 551 of the CFTR protein (p.Gly551Ser). This variant is present in population databases (rs121909013, gnomAD 0.003%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 1944451, 7606851, 23974870). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as 1783G>A. ClinVar contains an entry for this variant (Variation ID: 7142). 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. Experimental studies have shown that this missense change affects CFTR function (PMID: 11242048, 22293084). This variant disrupts the p.Gly551 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1379413, 1695717, 8605891, 19734299). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000224595	SCV001713426	pathogenic	not provided	2020-12-28	criteria provided, single submitter	clinical testing
Mendelics	RCV002247261	SCV002518679	pathogenic	Hereditary pancreatitis	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000007562	SCV002704675	pathogenic	Cystic fibrosis	2021-03-24	criteria provided, single submitter	clinical testing	The p.G551S pathogenic mutation (also known as c.1651G>A and 1783G>A), located in coding exon 12 of the CFTR gene, results from a G to A substitution at nucleotide position 1651. The glycine at codon 551 is replaced by serine, an amino acid with similar properties. This mutation was first described in two Caucasian siblings homozygous for this mutation with mild pulmonary symptoms, pancreatic sufficiency, and normal sweat chloride levels (Strong TV et al. N. Engl. J. Med., 1991 Dec;325:1630-4). This mutation has also been described in three Mexican siblings with mild pulmonary symptoms, pancreatic sufficiency, elevated sweat chloride levels, and the p.F508del mutation confirmed in trans (Orozco L et al. Clin. Genet., 1995 Feb;47:96-8). Codon 551 resides within nucleotide-binding domain 1 (NBD1) of the CFTR protein and in vitro functional studies have shown that the p.G551S mutation decreased chloride channel activity compared to the wild-type CFTR protein (Anderson MP et al. Science, 1992 Sep;257:1701-4; Yu H et al. J. Cyst. Fibros., 2012 May;11:237-45). Based on data from gnomAD, the A allele has an overall frequency of 0.02% (51/282242) total alleles studied. The highest observed frequency was 0.04% (51/128786) of European (non-Finnish) alleles. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003473020	SCV004213573	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-02-01	criteria provided, single submitter	clinical testing
OMIM	RCV000007562	SCV000027763	pathogenic	Cystic fibrosis	1991-12-05	no assertion criteria provided	literature only
Natera, Inc.	RCV001831533	SCV002080635	pathogenic	CFTR-related disorder	2017-08-28	no assertion criteria provided	clinical testing