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

dbSNP: rs113857788

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029537	SCV000052189	uncertain significance	not specified	2024-02-12	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.4056G>T (p.Gln1352His) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) 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 6e-05 in 251226 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing CFTR-Related Diseases (6e-05 vs 0.013), allowing no conclusion about variant significance. c.4056G>T has been reported in at least one homozygous patient with CBAVD (e.g., Claustres_2017). Another variant at this position, c.4056G>C (legacy c.4188 G>C), which encodes the same p.Gln1352His amino acid change, has been reported in the literature as well. The Gln1352His missense variant (in many cases without specifying nucleotide substitution) have been reported in individuals affected with multiple CFTR-Related Diseases, including chronic pancreatitis (e.g., Fujiki_2004, Lee_2003, Lee_2005, Keiles_2006, Nakano_2015, Cho_2016), Congenital Bilateral Absence of the Vas Deferens (CBAVD; e.g., Braekeleer_1996, Dork_1997, Danziger_2004, Ratbi_2007, Steiner_2011, Claustres_2017), and bronchiecstasis (e.g., Lee_2003). In at least several of these patients, a second pathogenic mutation in CFTR was identified, while in others, a second variant was not found. The variant has also been reported in individuals affected by severe asthma (e.g., Ngiam_2006), primary sclerosing cholangitis (e.g., Pall_2007), sarcoidosis (e.g., Makrythanasis_2010), impaired male fertility (e.g., Rudnik-Shoneborn_2021) and azoospermia (e.g., Ooi_2014). These reports do not contain co-segregation information definitively associating the variant with disease, however several case-control studies report a significant over-representation of the Gln1352His variant in individuals affected with chronic pancreatitis phenotypes (e.g., Lee_2003, Fujuiki_2004, Nakano_2015). The variant has also been reported as part of a complex allele with p.I807M in the compound heterozygous state with known pathogenic alleles in asymptomatic individuals (e.g., Claustres_2017). At least one publication reports experimental evidence evaluating an impact on protein function, indicating that variant results in defective protein expression and channel kinetics (e.g., Lee_2003). Collectively, the currently available information suggests that the Gln1352His variants could be associated with mild CFTR-related phenotypes, however further evidence such as co-segregation studies are needed to conclusively establish association with these CFTR-related diseases. The following publications have been ascertained in the context of this evaluation (PMID: 15716623, 22324837, 16596947, 32025909, 9239681, 27578509, 28603918, 15705292, 14998948, 9272157, 15121783, 20021716, 20052366, 28456595, 33502066, 17003641, 15829248, 12952861, 25880441, 20722470, 22664493, 31808782, 25492507, 15645635, 16678503, 27324553, 20558957, 24697796, 17719933, 25735457, 29805046, 17329263, 33374015, 18304229, 26708955, 21520337, 31940241, 16435054, 19812525, 29216686). ClinVar contains an entry for this variant (Variation ID: 35882). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757090	SCV000885195	pathogenic	not provided	2020-01-23	criteria provided, single submitter	clinical testing	The CFTR c.4056G>T; p.Gln1352His variant (rs113857788), and another variant resulting in the same amino acid change (c.4056G>C; p.Gln1352His), are reported in the literature in multiple individuals affected with CFTR-related disorders such as pancreatitis and congenital bilateral absence of the vas deferens (Anzai 2003, Claustres 2017, Lee 2003, Ratbi 2007). The p.Gln1352His variant is also reported to be enriched in Asian pancreatitis patients compared to unaffected individuals (Claustres 2005, Kondo 2015, Nakano 2015). Expression of the variant protein in a cell line reveals a significant reduction in mature CFTR protein detected compared to wildtype (Lee 2003). The c.4056G>T; p.Gln1352His variant is reported in ClinVar (Variation ID: 35882), and is found in the general population with an overall allele frequency of 0.006% (17/282620 alleles) 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, this 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. Claustres M et al. Molecular pathology of the CFTR locus in male infertility. Reprod Biomed Online. 2005 Jan;10(1):14-41. Claustres M et al. CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants. Hum Mutat. 2017 Oct;38(10):1297-1315. Kondo S et al. Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese. Am J Physiol Gastrointest Liver Physiol. 2015 Aug 15;309(4):G260-9. 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. Nakano E et al. Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis. Dig Dis Sci. 2015 May;60(5):1297-307. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000757090	SCV000888094	uncertain significance	not provided	2018-05-11	criteria provided, single submitter	clinical testing
Invitae	RCV000808411	SCV000948520	likely benign	Cystic fibrosis	2024-01-17	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000757090	SCV001713444	uncertain significance	not provided	2019-08-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002256007	SCV002529723	likely pathogenic	Hereditary pancreatitis	2021-05-24	criteria provided, single submitter	curation
Ambry Genetics	RCV000808411	SCV002631929	uncertain significance	Cystic fibrosis	2023-06-08	criteria provided, single submitter	clinical testing	The p.Q1352H variant (also known as c.4056G>T) is located in coding exon 25 of the CFTR gene. This alteration results from a G to T substitution at nucleotide position 4056. The glutamine at codon 1352 is replaced by histidine, an amino acid with highly similar properties. This same amino acid change has been reported in the literature as the result of a different underlying nucleotide substitution (c.4056G>C). The amino acid change was reported in 5 of 19 males with congenital bilateral absence of the vas deferens (CBAVD), one of which was a compound heterozygote for the p.W216* pathogenic mutation (Anzai C et al. 2003; J Cystic Fibrosis.; 2:14-18). The p.Q1352H substitution was found to be significantly associated with bronchiectasis in a small Korean population. In addition, in vitro functional studies showed that this amino acid substitution 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 Gen. 2003; 12(18):2321-2332). Other studies report an association with chronic pancreatitis or pulmonary disease, but these studies failed to control for confounding factors, analyze other potential genes, or reach statistical significance (Fujiki K et al. J Med Genet. 2004;41(5):e55; Ngiam N et al. J Cyst Fibrosis. 2006;5(3):159-164). A recent study found a strong association of this variant with chronic pancreatitis; of 193 patients tested, 10% carried this variant (p = 0.005) (Nakano et al 2015; Dig Dis Sci; 60(5):1297-307). This amino acid position is highly conserved on sequence alignment. This alteration is predicted to be deleterious by BayesDel in silico analysis. Based on available evidence, this variant is unlikely to be causative of classic CF; however, its clinical contribution to the development of a CFTR-related disorder in specific populations is uncertain.
PreventionGenetics, part of Exact Sciences	RCV004532409	SCV004116528	uncertain significance	CFTR-related disorder	2023-02-02	criteria provided, single submitter	clinical testing	The CFTR c.4056G>T variant is predicted to result in the amino acid substitution p.Gln1352His. This variant has been reported in the heterozygous state in patients with congenital bilateral absence of vas deferens (https://cftr.iurc.montp.inserm.fr/cgi-bin/affiche.cgi?variant=c.4056G>T; Table 2 and 4 in Claustres. 2017. PubMed ID: 28603918). This variant is reported in 0.046% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117304834-G-T). A different nucleotide change that results in the same amino acid change (c.4056G>C, p.Gln1352His) has been reported on extensively in the literature. The c.4056G>C, p.Gln1352His variant has been reported in patients with several different phenotypes including asthma, alcoholic chronic pancreatitis, idiopathic chronic pancreatitis, azoospermic males, and bronchiectasis (Cho. 2016. PubMed ID: 27578509; Gallati. 2009. PubMed ID: 20021716; Kondo. 2015. PubMed ID: 26089335; Pall. 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 (~1.3% in East Asians, http://gnomad.broadinstitute.org/variant/7-117304834-G-C). 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. 2004. PubMed ID: 15121783; Ngiam. 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. The c.4056G>T has conflicting interpretations in ClinVar ranging from likely benign to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/35882). In summary, it is possible that the p.Gln1352His variant is associated with mild CFTR-related phenotypes or exhibits reduced penetrance . However, without additional conclusive evidence, the clinical significance of this variant remains uncertain.