ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.4056G>T (p.Gln1352His) (rs113857788)

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Total submissions: 5
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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 2020-11-03 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 domain 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, predominantly at a frequency of 0.00046 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.00046 vs 0.013), allowing no conclusion about variant significance. 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. The Gln1352His variants (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. 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 in healthy controls, including in the compound heterozygous state with known pathogenic alleles in at least three apparently asymptomatic individuals (e.g. Bienvenu_2005, Claustres_2017). 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), and azoospermia (e.g. Ooi_2014). The variant did not segregate with disease in a family with cystic fibrosis (CF), in which the proband carried Gln1352His, Phe508Del, and Tyr122X variants, as two healthy, unaffected family members with the p. Gln1352His variant also carried pathogenic p.Tyr122X in a compound heterozygous state (Bienvenu_2005). 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. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance (n=1) and pathogenic/ likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282161 SCV000885195 pathogenic none 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 2020-09-07 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000757090 SCV001713444 uncertain significance not provided 2020-04-10 criteria provided, single submitter clinical testing

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