ClinVar Miner

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

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Total submissions: 13
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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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 2020-05-08 criteria provided, single submitter clinical testing The 5T variant, located in intron 9 of the CFTR gene, is an alteration within the poly-thymidine tract, which decreases the efficiency of exon 10 splicing. The 5T variant in trans with a pathogenic CFTR mutation, or in the homozygous state, has been associated with CFTR-related disorders, including bronchiectasis (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98), acute recurrent or chronic pancreatitis (Werlin S et al. J. Pediatr. Gastroenterol. Nutr., 2015 May;60:675-9; Masson E et al. PLoS ONE, 2013 Aug;8:e73522), and congenital bilateral absence of the vas deferens (CBAVD) (Bombieri C et al. J. Cyst. Fibros., 2011 Jun;10 Suppl 2:S86-102). The effect of 5T on exon 10 splicing is influenced by the adjacent TG tract, which usually consists of 11, 12, or 13 TG repeats. Increasing TG tract length correlates with decreased amount of full-length CFTR, thereby leading to higher likelihood of a cystic fibrosis phenotype (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98); information regarding the number of TG repeats adjacent to the 5T allele is limited in pancreatitis and bronchiectasis research (Mantovani V et al. Clin. Chem., 2007 Mar;53:531-3; Bombieri C et al. J. Cyst. Fibros., 2011 Jun;10 Suppl 2:S86-102).
CeGaT Praxis fuer Humangenetik Tuebingen RCV000381834 SCV001501415 pathogenic not provided 2021-03-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV001329936 SCV001521501 pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 2019-09-02 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae RCV000309488 SCV001591258 pathogenic Cystic fibrosis 2020-11-02 criteria provided, single submitter clinical testing This sequence change, also referred to as 5T;TG12 or TG12-5T in the literature, consists of 12 TG and 5 T sequence repeats on the same chromosome, and is located in intron 9 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. The TG[12]T[5] allele has been observed in males with congenital bilateral absence of the vas deferens (CBAVD) and in both males and females with cystic fibrosis (CF) when homozygous or present on the opposite chromosome (in trans) from a severe pathogenic CFTR variant (PMID: 14685937). In males, the overall penetrance of this allele, when in trans with a severe pathogenic CFTR variant, is expected to be ~93%, with CBAVD accounting for ~94% of cases and CF (i.e. elevated sweat chloride and respiratory disease) accounting for ~6% of cases. The penetrance of CF in females is expected to be about 6% when in trans with a severe pathogenic variant (PMID: 14685937, 27447098). Experimental studies demonstrate that the 5T allele leads to exclusion of exon 10 (referred to as exon 9 in some publications) from the mRNA, which ultimately results in a non-functional CFTR protein (PMID: 7691356, 7684641, 10556281, 14685937, 21658649). Importantly, the number of TG repeats (11, 12 or 13) modifies the extent of exon 10 skipping when in cis with the 5T allele (PMID: 14685937, 10556281, 9435322). In a mini-gene assay, the percentage of CFTR mRNA without exon 10 was 54% for TG[11]T[5], 72% for TG[12]T[5] and 100% for TG[13]T[5] (PMID: 10556281). For these reasons, this TG[12]T[5] variant has been classified as Pathogenic.
Nilou-Genome Lab RCV000309488 SCV001737338 pathogenic Cystic fibrosis 2021-06-10 criteria provided, single submitter clinical testing
GeneDx RCV000381834 SCV001778496 pathogenic not provided 2021-05-24 criteria provided, single submitter clinical testing Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 31180159, 15070876, 19812525, 20977904, 22842702, 27447098, 18616886, 17314234, 26253411, 23416327, 28546993, 29997923, 23092102, 20560922, 26989879, 29216686, 26500004, 28174639, 27488005, 25383785, 27996019, 16778595, 17394391, 12068373, 14993601, 18306312, 1381723, 7684646, 7506096, 7573058, 9435322, 23951356, 25033378, 18507830, 7739684, 22427236, 22430190, 14685937, 28801929, 28152038, 23554779)
Suma Genomics RCV000309488 SCV001847728 uncertain significance Cystic fibrosis criteria provided, single submitter clinical testing

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