Submissions for variant NM_000492.4(CFTR):c.532G>A (p.Gly178Arg)

gnomAD frequency: 0.00002  dbSNP: rs80282562

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056394	SCV000071500	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
PharmGKB	RCV000211246	SCV000268409	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508034	SCV000601125	pathogenic	not provided	2017-05-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763153	SCV000893740	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004435	SCV001163480	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000056394	SCV001169310	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Ambry Genetics	RCV000056394	SCV001185879	pathogenic	Cystic fibrosis	2023-04-19	criteria provided, single submitter	clinical testing	The p.G178R pathogenic mutation (also known as c.532G>A and 664G>A), located in coding exon 5 of the CFTR gene, results from a G to A substitution at nucleotide position 532. The glycine at codon 178 is replaced by arginine, an amino acid with dissimilar properties. This mutation was originally described in a Canadian family with cystic fibrosis (Zielenski J et al, Genomics 1991 May; 10(1):229-35). Subsequently, a homozygous p.G178R mutation was identified in a French individual with cystic fibrosis (Claustres M et al, Hum. Mutat. 2000; 16(2):143-56). In addition, this pathogenic mutation was found in 50 individuals with cystic fibrosis and was associated with high sweat chloride levels and pancreatic insufficiency (Sosnay PR et al, Nat. Genet. 2013 Oct; 45(10):1160-7). In vitro functional studies showed that G178R mutant protein is processed and matures normally, but has reduced chloride channel activity (Seibert FS et al, Biochemistry 1997 Sep; 36(39):11966-74; Sosnay PR et al, Nat. Genet. 2013 Oct; 45(10):1160-7). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Myriad Genetics, Inc.	RCV000056394	SCV001194201	pathogenic	Cystic fibrosis	2019-12-04	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.532G>A(G178R) is classified as pathogenic in the context of cystic fibrosis and is associated with classic disease. Sources cited for classification include the following: PMID 18456578, 9305991, 23381846 and 23974870. Classification of NM_000492.3(CFTR):c.532G>A(G178R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056394	SCV001363743	pathogenic	Cystic fibrosis	2022-10-24	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.532G>A (p.Gly178Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. One computational tool predict the variant creates a 3' acceptor site. Consistent with this prediction, one functional study showed that this variant led to a significant skipping of exon 5 (Raynal_2013). The variant allele was found at a frequency of 1.2e-05 in 168188 control chromosomes. c.532G>A has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Zielenski_1991, Cremonesi_1992, Heim_2001, Sugarman_2004, Ooi_2012, Sosnay_2013, DeBoeck_2014). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function (Seibert_1997, Choi_2001, Yu_2012, Sosnay_2013). The most pronounced variant effect results in <10% of normal activity. Eleven 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056394	SCV001581522	pathogenic	Cystic fibrosis	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 178 of the CFTR protein (p.Gly178Arg). This variant is present in population databases (rs80282562, gnomAD 0.003%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 1710599, 15638824, 23974870, 29133775). 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: 48692). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 9305991). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000508034	SCV002019248	pathogenic	not provided	2021-05-13	criteria provided, single submitter	clinical testing
Mendelics	RCV002247425	SCV002518668	pathogenic	Hereditary pancreatitis	2022-05-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473296	SCV004213481	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-11-27	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000056394	SCV004239038	pathogenic	Cystic fibrosis	2023-12-01	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Natera, Inc.	RCV001831713	SCV002082506	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001831713	SCV005362857	pathogenic	CFTR-related disorder	2024-03-22	no assertion criteria provided	clinical testing	The CFTR c.532G>A variant is predicted to result in the amino acid substitution p.Gly178Arg. This variant, also known as c.664G>A in literature, has been reported along with a second pathogenic variant in multiple individuals with Cystic Fibrosis (Zielenski et al. 1991. PubMed ID: 1710599; Ooi et al. 2012. PubMed ID: 22658665; Raraigh et al. 2021. PubMed ID: 34782259; Sosnay PR et al 2013. PubMed ID: 23974870; https://cftr2.org/mutation/scientific/G178R/). In vitro functional studies suggest this variant impairs CFTR chloride channel function (Seibert et al. 1997. PubMed ID: 9305991; Choi et al. 2001. PubMed ID: 11242048). This variant is reported in 0.0035% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.