Submissions for variant NM_000492.4(CFTR):c.4056G>C (p.Gln1352His)

dbSNP: rs113857788

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000007659	SCV000075079	benign	Cystic fibrosis	2024-01-31	criteria provided, single submitter	clinical testing
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000007659	SCV000267254	uncertain significance	Cystic fibrosis	2016-03-18	criteria provided, single submitter	reference population
Eurofins Ntd Llc (ga)	RCV000586028	SCV000331812	uncertain significance	not provided	2017-11-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001009487	SCV000466528	likely benign	CFTR-related disorder	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586028	SCV000603061	pathogenic	not provided	2019-10-11	criteria provided, single submitter	clinical testing	The CFTR c.4056G>C; p.Gln1352His variant (rs113857788) has been reported in multiple individuals diagnosed with CFTR-related disorders, such as congenital bilateral absence of vas deferens (Anzai 2003, Danziger 2004, Ratbi 2007, Steiner 2011, Li 2012) and pancreatitis (Lee 2003, Keiles 2006). In multiple affected individuals, this variant has been found in trans to other pathogenic CFTR variants (Anzai 2003, Steiner 2011, Li 2012). It has also been observed at a significantly higher frequency in Asian pancreatitis patients than unaffected individuals (Lee 2003, Fujiki 2004). Expression of the variant protein in a cell line reveals a significant reduction in mature CFTR protein detected compared to wildtype (Lee 2003). The variant is listed in ClinVar (Variation ID: 7237) and is observed in the general population database at a frequency of 0.1% (275/282620 alleles, including three homozygotes) in the Genome Aggregation Database. The glutamine at residue 1352 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict that the variant is deleterious. Based on available information, the variant is considered to be mildly pathogenic. References: Anzai C et al. CFTR gene mutations in Japanese individuals with congenital bilateral absence of the vas deferens. J Cyst Fibros. 2003 2(1):14-8. Danziger K et al. Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis. Hum Reprod. 2004 19(3):540-6. Fujiki K et al. Genetic evidence for CFTR dysfunction in Japanese: background for chronic pancreatitis. J Med Genet. 2004 41(5):e55. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 33(3):221-7. Lee J et al. A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. Hum Mol Genet. 2003 12(18):2321-32. Li H et al. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. J Cyst Fibros. 2012 11(4):316-23. Ratbi I et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod. 2007 22(5):1285-91. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 32(8):912-20.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375489	SCV000696997	uncertain significance	not specified	2023-12-04	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.4056G>C (p.Gln1352His) 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 0.00066 in 1619220 control chromosomes, predominantly at a frequency of 0.019 within the East Asian subpopulation in the gnomAD database, including 16 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis phenotype (0.013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant was found with even higher allele frequencies in several East Asian subpopulations, e.g. in the Japanese (with an allele frequency of 0.023 from about 14,000 healthy Japanese individuals in the jMorp database [PMID: 33179747]) and in the Vietnamese (with an allele frequency of 0.05 in 406 unrelated healthy Kinh Vietnamese individuals [PMID: 31180159]), suggesting this variant may be a benign polymorphism found primarily in East Asian populations. On the other hand, the c.4056G>C variant is frequently reported in men with CBAVD in conjunction with a second pathogenic variant, especially the 5T allele. However, one study reported the variant in two unaffected siblings who also carried a pathogenic CFTR mutation in trans (p.Y122X), including an apparently fertile male, suggesting the variant may not be fully penetrant or is not pathogenic (Bienvenu_2005). A recent study found the variant in 32/276 Chinese CAVD patients (i.e. with an allele frequency of 5.98%, including 1 homozygote), and in only 1 allele from 50 control individuals (Luo_2021). This variant is also seen with other phenotypes such as CF, pancreatitis, asthma, nontuberculous mycobacterial lung disease, and bronchiectasis, and the risk association score from several independent publications suggest that this variant is possibly associated with these CF-related phenotypes. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-30% of normal activity (Lee_2003). The following publications have been ascertained in the context of this evaluation (PMID: 15463840, 16596947, 17539902, 28603918, 9272157, 15121783, 20021716, 29997923, 17003641, 33663443, 31180159, 12952861, 22483971, 32777524, 25492507, 16678503, 20558957, 29520692, 17329263, 33374015, 31682332, 21520337, 28608624, 19812525, 20233062). Fifteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=3), pathogenic/likely pathogenic (n=3) and VUS (n=9). Based on the evidence outlined above, the variant was classified as VUS.
Mendelics	RCV000007659	SCV001137498	uncertain significance	Cystic fibrosis	2019-05-28	criteria provided, single submitter	clinical testing
CFTR-France	RCV001009487	SCV001169582	pathogenic	CFTR-related disorder	2018-01-29	criteria provided, single submitter	curation
Ambry Genetics	RCV000007659	SCV001183420	uncertain significance	Cystic fibrosis	2023-09-01	criteria provided, single submitter	clinical testing	The p.Q1352H variant (also known as c.4056G>C), located in coding exon 25 of the CFTR gene, results from a G to C substitution at nucleotide position 4056. The glutamine at codon 1352 is replaced by histidine, an amino acid with highly similar properties. The variant has been reported in multiple Asian individuals with CFTR-related findings, including congenital absence of the vas deferens, chronic pancreatitis, and pulmonary disease cohorts; a few individuals were homozygotes and several had additional CFTR variants also detected (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77; Anzai C et al. J. Cyst. Fibros., 2003 Mar;2:14-8; Lee JH et al. Hum. Mol. Genet., 2003 Sep;12:2321-32; Oka H et al. Intern Med, 2010 Jun;49:1251-2; Qiu L et al. Front Med, 2018 Oct;12:550-558; Iso M et al. Hum Genome Var, 2019 Apr;6:17; Yuan P et al. Andrology, 2019 05;7:329-340). In addition, in vitro functional studies showed that this variant results in a 70-80% reduction in the expression of the mature glycosylated CFTR protein and in chloride channel activity (Lee JH et al. Hum. Mol. Genet., 2003 Sep;12:2321-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, this variant is unlikely to be causative of classic cystic fibrosis; however, its contribution to the development of a CFTR-related disorder is uncertain. This alteration is thus classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000586028	SCV001713443	uncertain significance	not provided	2023-05-09	criteria provided, single submitter	clinical testing	PP3, PM3
Johns Hopkins Genomics, Johns Hopkins University	RCV000007659	SCV001905498	likely benign	Cystic fibrosis	2021-09-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586028	SCV002047115	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.018 (67/3806 chromosomes in Korean subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Although the variant has been identified in individuals described as having CF in the published literature (PMIDs: 16596947 (2005), 20558957 (2010), 31136843 (2019), 36409994 (2022)), this variant is likely not associated with classic CF, but it may be associated with CFTR-related diseases such as congenital bilateral absence of the vas deferens (CBAVD) (PMIDs: 28603918 (2017), 30811104 (2019), 32777524 (2021), 34673937 (2021), 35119551 (2022)), bronchiectasis (PMIDs: 12952861 (2003), 29997923 (2018)), and pancreatitis (PMIDs: 16187186 (2005), 32352720 (2020)). In addition, in vitro studies have reported that this variant has a deleterious effect on CFTR protein expression and channel activity (PMID: 12952861 (2003)), however, further research is needed.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000007659	SCV002507388	uncertain significance	Cystic fibrosis	2021-05-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000586028	SCV002538698	uncertain significance	not provided	2022-06-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced chloride channel activity and chloride/bicarbonate exchange activity (Lee 2003); Although this variant has not been reported in the homozygous or compound heterozygous state in individuals with cystic fibrosis, it has been reported in individuals of Asian ancestry with CFTR-related disorders (Gallati 2009, Steiner 2011, Cho 2016, Luo 2021); Some case control studies suggest this variant may be associated with pancreatitis in the Asian population (Fujiki 2004, Nakano 2015, Zou 2018, Iso 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27578509, 21520337, 16678503, 20981092, 20021716, 16187186, 30420730, 25492507, 17719933, 26089335, 28608624, 30450785, 28687971, 15121783, 31180159, 35119551, 12952861, 23514810, 33663443, 32777524, 30992994)
PreventionGenetics, part of Exact Sciences	RCV001009487	SCV004115982	uncertain significance	CFTR-related disorder	2024-01-18	criteria provided, single submitter	clinical testing	The CFTR c.4056G>C variant is predicted to result in the amino acid substitution p.Gln1352His. This variant has been reported in patients with several different phenotypes including asthma, alcoholic chronic pancreatitis, idiopathic chronic pancreatitis, azoospermic males, and bronchiectasis (Cho et al. 2016. PubMed ID: 27578509; Gallati et al. 2009. PubMed ID: 20021716; Kondo et al. 2015. PubMed ID: 26089335; Pall et al. 2007. PubMed ID: 17719933). The c.4056G>C (p.Gln1352His) variant has been found at higher rates in Asian patients with pancreatitis (12.3%) compared to unaffected controls (3.7%) (Fujiki et al. 2004. PubMed ID: 15121783). However, the majority of these studies were conducted in Eastern Asian population cohorts where the c.4056G>C variant is found at a higher allele frequency. Functional studies in CHO cell lines indicate the p.Gln1352His change decreases CFTR protein expression and chloride channel function (Lee et al. 2003. PubMed ID: 12952861; Fujiki et al. 2004. PubMed ID: 15121783; Ngiam et al. 2006. PubMed ID: 16678503). However, no family studies have been conducted to determine if the c.4056G>C variant segregates with disease in individual families and to our knowledge, no homozygous c.4056G>C individuals have been reported with a CFTR-related disorder. This variant has been observed with a minor allele frequency of ~1.3% in East Asians, including 3 homozygous individuals (http://gnomad.broadinstitute.org/variant/7-117304834-G-C). The c.4056G>C has several conflicting interpretations in ClinVar ranging from benign to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/7237). It is possible that the c.4056G>C variant exhibits incomplete penetrance or is a risk allele for disease. However, without additional conclusive evidence, the clinical significance of this variant remains uncertain.
OMIM	RCV000007659	SCV000027860	pathogenic	Cystic fibrosis	2003-09-15	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001009487	SCV002507474	likely pathogenic	CFTR-related disorder	2021-05-12	no assertion criteria provided	clinical testing