Submissions for variant NM_000492.4(CFTR):c.92G>T (p.Arg31Leu)

gnomAD frequency: 0.00010  dbSNP: rs149353983

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000577473	SCV001981583	uncertain significance	Cystic fibrosis	2017-03-03	reviewed by expert panel	research
Counsyl	RCV000577473	SCV000795721	uncertain significance	Cystic fibrosis	2017-11-13	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000733631	SCV000861719	uncertain significance	not provided	2018-06-07	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000577473	SCV001425298	uncertain significance	Cystic fibrosis	2019-03-01	criteria provided, single submitter	clinical testing	This variant has been previously reported in patients with a phenotypic consistent with cystic fibrosis and is currently classified as a variant of uncertain significance by three submitters in ClinVar. Functional studies have shown that this variant may lead to reduced protein function, however the impact of this variant is not completely understood at this time. Additionally, this CFTR variant (rs149353983) is rare (<0.1%) in large population datasets (gnomAD: 11/282294 total alleles; 0.0039%; no homozygotes). Two bioinformatic tools queried predict that this substitution would be tolerated, and the arginine residue at this position is evolutionarily conserved across most species assessed. The clinical significance of c.92G>T is uncertain at this time.
Mayo Clinic Laboratories, Mayo Clinic	RCV000733631	SCV001714822	uncertain significance	not provided	2021-03-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257391	SCV002529742	uncertain significance	Hereditary pancreatitis	2021-04-30	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281740	SCV002570630	uncertain significance	not specified	2024-07-11	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.92G>T (p.Arg31Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251968 control chromosomes. c.92G>T has been reported in the literature as a heterozygous non-informative genotype (second allele not specified) in a 24 year old initially reported with pulmonary symptoms at age 5.7 years but virtually normal pulmonary and pancreatic functions at age 24 despite an elevated sweat chloride level (90.8 mmol/L) (example, Zielenski_1995); in compound heterozygosity with p.F508del in at-least 7 individuals with a mean sweat chloride level of 37 mmol/L in the CFTR-2 database (example, McCague_2019, Munck_2020); a non-informative genotype in the South African CF registry (SACFR) (example, Zampoli_2021). These data do not allow any conclusion about variant significance. At least three publications report conflicting experimental evidence evaluating an impact on protein function in-vitro (example, Jurkuvenalte_2006, Raraigh_2018, Bihler_2024). The most pronounced variant effect results in diminished channel activity compared to wild-type (<10% of WT) in one study (Jurkuvenalte_2006), an indeterminate level of channel activity (56% of WT) in another (Raraigh_2018) and approximately (Gt channel conductance) 22% of normal chloride channel conductance relative to wild type (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 18193900, 17098864, 18306312, 17235394, 17098482, 7526685, 16251901, 31036917, 38388235, 16339147, 30888834, 15536480, 31916691, 29805046, 34996830, 34583889, 34350279, 7537150). ClinVar contains an entry for this variant (Variation ID: 54087). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Ambry Genetics	RCV000577473	SCV002686699	uncertain significance	Cystic fibrosis	2024-07-29	criteria provided, single submitter	clinical testing	The p.R31L variant (also known as c.92G>T), located in coding exon 2 of the CFTR gene, results from a G to T substitution at nucleotide position 92. The arginine at codon 31 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in an individual with elevated sweat chloride levels and virtually normal pulmonary and pancreatic function; however, no second CFTR alteration was identified (Zielenski J, Hum. Mutat. 1995; 5(1):43-7). In vitro protein studies show that this alteration causes a reduction in the surface expression of the CFTR protein (Jurkuvenaite A, J. Biol. Chem. 2006 Feb; 281(6):3329-34; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002490617	SCV002779633	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-05-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577473	SCV003517738	uncertain significance	Cystic fibrosis	2024-08-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 31 of the CFTR protein (p.Arg31Leu). This variant is present in population databases (rs149353983, gnomAD 0.008%). This missense change has been observed in individuals with cystic fibrosis (PMID: 12454843, 28392015, 30888834, 31916691, 34350279). ClinVar contains an entry for this variant (Variation ID: 54087). 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: 16339147). 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.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577473	SCV000679484	not provided	Cystic fibrosis		no assertion provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000581319	SCV000692318	uncertain significance	Lung disease, non-specific	2015-06-17	no assertion criteria provided	clinical testing