ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1210-11T>G (rs73715573)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000155471 SCV000205163 likely pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2014-05-01 criteria provided, single submitter clinical testing The c.1210-34TG[12]T[5] in intron 9 of CFTR is a variant of the polymorphic TG[n ]T[m] region adjacent to exon 10. The TG[12]T[5] allele has been identified in 5 .9% (17/290) of Ashkenazi Jewish chromosomes, 3% (47/1472) of East Asian chromos omes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.or g/), and is known to affect mRNA splicing (Chu 1993). Studies have shown that lo nger TG repeat sizes (TG11, 12 and 13) in individuals with T[5] have a greater s usceptibility to disease than those with smaller TG repeat sizes when present in trans with a pathogenic CFTR variant (Chu 1992, Cuppens 1998, Groman 2004, Radp our 2007). The associated CF-related symptoms are congenital bilateral absence o f the vas deferens (CBAVD), male infertility, mild to classic forms of cystic fi brosis, with severity depending of the CF variant on the opposite allele (Chillo n 1995). In summary, the 1210-34TG[12]T[5] variant is likely pathogenic, though additional studies are required to fully establish its clinical significance. AC MG/AMP Criteria applied: PM3_Strong, PP3, PP4.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000381834 SCV000331080 other not provided 2016-05-19 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001095145 SCV000466510 uncertain significance CFTR-related disorders 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507057 SCV000603012 pathogenic not specified 2017-06-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000309488 SCV000696826 pathogenic Cystic fibrosis 2020-04-09 criteria provided, single submitter clinical testing Variant summary: CFTR c. c.1210-11T>G occurs in the poly T tract between the branch site and the acceptor site in intron 9 (legacy intron 8) of CFTR. This combined poly-T and TG tract genotype is also designated as TG12-5T. Variants that disrupt this tract (commonly referred to as "5T" variants, also called "c.1210-12T[5]" or "c.1210-7_1210-6del") have frequently been associated with CFTR-related diseases when found in compound heterozygosity with other pathogenic mutations in CFTR. CFTR c.1210-11T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, at least one functional study shows a moderate impact to proper CFTR mRNA expression by altering the splicing efficiency of exon 9 in vitro (Hefferon_2004). The variant allele was found at a frequency of 0.0086 in 237638 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing CFTR-related diseases allowing no conclusion about variant significance. Similar 5T variants have been reported in the literature in numerous individuals affected with CF, CBAVD, and other CFTR-related diseases, but have also been found in unaffected controls when in compound heterozygosity with other pathogenic mutants in CFTR. (examples- Cuppens_1998, Noone_2001, Groman_2004, Sun_2006, Ratbi_2007, Tomaiudo_2010, Ballard_2015). The penetrance of 5T variants is influenced by the presence of other CFTR variants (e.g. p.R117H) and the length of the adjacent TG tract on the same allele (in cis). In most 5T CFTR genes, the number of TG repeats found in cis determines whether the amount of functional CFTR proteins that will be translated does fall above or below the critical level for normal CFTR function (Castellani_2008). Approximately 90% of the 5T CFTR genes found in CBAVD patients associate with TG12 or TG13, while about 10% associate with TG11 (Castellani_2008). In compound heterozygosity with a CF-causing mutation, or in homozygosity, R117H-5T generally results in pancreatic sufficient CF. A TG12-5T or TG13-5T CFTR gene found in compound heterozygosity with a CF-causing mutation, or possibly even in homozygosity, will in general result in a CFTR-related disorder, such as Congenital Bilateral Absence of the Vas Deferens (CBAVD) or chronic idiopathic pancreatitis. Some CBAVD patients may develop mild lung symptoms. In exceptional cases, TG12-5T and TG13-5T, may cause a mild form of CF. Three of five other ClinVar submitters (evaluation after 2014) have cited the variant as pathogenic. In addition, ACMG guidelines for reporting CFTR mutations consider the 5T allele as associated as a trans mutation in CBAVD (ACMG guideline_2011). Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics RCV000309488 SCV001137474 pathogenic Cystic fibrosis 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001010355 SCV001170538 pathogenic Inborn genetic diseases 2019-03-27 criteria provided, single submitter clinical testing Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;Other strong data supporting pathogenic classification

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