ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000007659 SCV000075079 benign Cystic fibrosis 2020-12-04 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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000586028 SCV000331812 uncertain significance not provided 2017-11-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001009487 SCV000466528 likely benign CFTR-related disorders 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 RCV000664322 SCV000603061 pathogenic none 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 2021-04-14 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 0.0015 in 256420 control chromosomes, predominantly at a frequency of 0.013 within the East Asian subpopulation in the gnomAD database, including 3 homozygotes. This frequency is approximately equal to the maximum expected frequency for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (0.013 vs 0.013), allowing no clear conclusion about variant significance, but suggesting this variant may be a benign polymorphism found primarily in East Asian populations. The c.4056G>C variant has been reported in the literature in multiple individuals affected with congenital bilateral absence of the vas deferens (CBAVD). The variant is frequently found 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). 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). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (4 VUS, 2 benign/likely benign, 2 pathogenic). The variant is reported in French Guidelines for clinical management and follow-up of infants with inconclusive CF diagnosis through newborn screen as a "mutation that result in a CFTR-related disorder CFTR-RD mutations" (Sermet-Gaudelus_2017). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Mendelics RCV000007659 SCV001137498 uncertain significance Cystic fibrosis 2019-05-28 criteria provided, single submitter clinical testing
CFTR-France RCV001009487 SCV001169582 pathogenic CFTR-related disorders 2018-01-29 criteria provided, single submitter curation
Ambry Genetics RCV001021765 SCV001183420 uncertain significance Inborn genetic diseases 2020-07-10 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. T<span style="background-color:initial">he 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 (D&ouml;rk T et al. Hum. Genet., 1997 Sep;100:365-77; Anzai C et al. J. Cyst. Fibros., 2003 Mar;2:14-8<span style="background-color:initial">; Lee JH et al. Hum. Mol. Genet., 2003 Sep;12:2321-32; Iso M et al. Hum Genome Var, 2019 Apr;6:17; Yuan P et al. Andrology, 2019 05;7:329-340<span style="background-color:initial">). In addition, in vitro<span style="background-color:initial"> 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<span style="background-color:initial">). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.<span style="background-color:initial"> Based on available evidence, this variant is unlikely to be causative of classic cystic fibrosis; however, its clinical contribution to the development of a CFTR-related disorder in specific populations is uncertain.
Mayo Clinic Laboratories, Mayo Clinic RCV000586028 SCV001713443 uncertain significance not provided 2019-10-08 criteria provided, single submitter clinical testing
OMIM RCV000007659 SCV000027860 pathogenic Cystic fibrosis 2003-09-15 no assertion criteria provided literature only

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