ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.532G>A (p.Gly178Arg) (rs80282562)

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Total submissions: 10
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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 2018-03-23 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
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 RCV001023935 SCV001185879 pathogenic Inborn genetic diseases 2019-04-19 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 Women's Health, 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 2019-04-05 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. Four 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.
Invitae RCV000056394 SCV001581522 pathogenic Cystic fibrosis 2020-03-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 178 of the CFTR protein (p.Gly178Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs80282562, ExAC 0.003%). This variant has been observed in individual(s) with cystic fibrosis (PMID: 23974870, 1710599, 15638824, 29133775). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 48692). This variant has been reported to affect CFTR protein function (PMID: 9305991). For these reasons, this variant has been classified as Pathogenic.

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