ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1210-12T[5] (rs1805177)

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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 RCV000155619 SCV000205327 uncertain significance not specified 2016-01-14 criteria provided, single submitter clinical testing The c.1210-34TG[11]T[5] in intron 9 of CFTR is a variant of the polymorphic TG[n ]T[m] region adjacent to exon 10. The T[5] allele has been identified in an ave rage of 4.3% of individuals from a population of European American chromosomes ( Groman 2004) and has been shown to affect splicing in small percentage of transc ripts (Chu 1993). The length of the TG tract modifies the overall risk with lon ger TG repeat sizes (TG 12 and 13) showing the greatest susceptibility to diseas e when present in trans with a pathogenic cystic fibrosis variant (Chu 1992, Cup pens 1998, Groman 2004, Radpour 2007). The combination of the T[5] and TG[11] is least likely to exhibit an abnormal phenotype but a modest increased risk canno t be excluded (Cuppens 1998; Groman 2004). The associated CF-related symptoms ar e congenital bilateral absence of the vas deferens (CBAVD), male infertility, mi ld to classic forms of cystic fibrosis, with severity depending of the CF varian t on the opposite allele (Chillon 1995). In summary, the clinical significance o f the 1210-34TG[11]T[5] is uncertain.
GeneDx RCV000405075 SCV000329660 pathogenic not provided 2017-07-14 criteria provided, single submitter clinical testing The c.1210-7_1210-6delTT variant in the CFTR gene, also reported as c.1210-12T[5] and commonly referred to as the 5T allele, occurs in the poly T tract in intron 9 (intron 8 using legacy exon numbering). The c.1210-7_1210-6delTT variant acts as a disease susceptibility variant with variable penetrance (CFTR2 Mutation Database; Ong et al., 2017). Specifically, the c.1210-7_1210-6delTT variant has been associated with recessive CFTR-related disorders when seen in trans with another severe pathogenic variant in the CFTR gene. Disease features described include elevated sweat chloride levels, congenital bilateral absence of the vas deferens (CBAVD) in males, and non-classic to classic cystic fibrosis (Chillon et al., 1995; Ong et al., 2017). However, the penetrance of the c.1210-7_1210-6delTT variant is influenced by the presence of other variants (e.g. R117H) and the length of the adjacent TG tract on the same allele (in cis). Longer TG repeat sizes (TG12 and TG13) in cis with c.1210-7_1210-6delTT are associated with a greater susceptibility to disease than c.1210-7_1210-6delTT in cis with a smaller TG repeat size (TG11) (Cuppens et al., 1998; Groman et al., 2004; Ong et al., 2017). RNA studies demonstrate that the c.1210-7_1210-6delTT variant results in abnormal splicing of exon 10 in a significant percentage of transcripts (Chu et al., 1993; Hefferon et al., 2002). The c.1210-7_1210-6delTT variant has been observed in at least 5% of alleles from of individuals of European background (Chillon et al., 1995). Therefore, based on the information available, we interpret c.1210-7_1210-6delTT as a pathogenic susceptibility variant with variable penetrance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000405075 SCV000331631 pathogenic not provided 2017-03-17 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000173692 SCV000466508 likely benign Cystic fibrosis 2016-06-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000155619 SCV000602990 pathogenic not specified 2017-06-17 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000405075 SCV000693251 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000173692 SCV000886265 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
CFTR-France RCV001009378 SCV001169231 pathogenic Cystic fibrosis; CFTR-related disorders 2018-01-29 criteria provided, single submitter curation when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Ambry Genetics RCV001010359 SCV001170545 pathogenic Inborn genetic diseases 2019-02-14 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
Myriad Women's Health, Inc. RCV000173692 SCV001193799 pathogenic Cystic fibrosis 2019-10-18 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.1210-7_1210-6delTT(aka IVS8-5T or 5T) is a variant within the polyT tract located within intron 8 of the CFTR gene. 5T has been observed in individuals diagnosed with cystic fibrosis but has also been observed in healthy individuals (PMID 23974870; gnomAD: AFR 7.085%). Please note that 5T is not associated with cystic fibrosis when detected in isolation and the American College of Medical Genetics does not recommend reporting 5T status through routine carrier screening when detected in isolation. However, 5T is considered an incompletely penetrant pathogenic variant that may result in cystic fibrosis when present on the same chromosome as R117H and combined with another pathogenic CFTR variant on the other chromosome. In the absence of R117H, 5T may be associated with CFTR-related disorders depending on the presence of other deleterious variants in the gene. In summary, classification of 5T is based on the following criteria: high frequency variant with incomplete penetrance and variable severity dependent on the presence of other variants in the CFTR gene. Please note: this allele was assessed in the context of healthy population screening.
Integrated Genetics/Laboratory Corporation of America RCV000007609 SCV001362614 pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 2019-11-04 criteria provided, single submitter clinical testing Variant summary: CFTR c.1210-12[5] (also known as c.5T_TG11 or c.1210-7_1210-6delTT) occurs in the poly T tract in intron 9. 5/5 computational tools predict no significant impact on normal splicing. However, at least one functional study shows a moderate impact to proper CFTR mRNA expression in vitro (Hefferon_2004). The variant has been reported in the literature in numerous individuals affected with Congenital Bilateral Absence of the Vas Deferens, as well as some individuals who are asymptomatic. The variant is associated with CFTR-related disorders when in trans with another severe pathogenic CFTR variant. The penetrance of the c.1210-12[5] variant is influenced by the presence of other variants (e.g. R117H) and the length of the adjacent TG tract on the same allele (in cis). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, four of which classified 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 for CBAVD and CFTR-related disorders.
OMIM RCV000007609 SCV000027810 pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 2008-05-28 no assertion criteria provided literature only
OMIM RCV000007610 SCV000053489 risk factor Bronchiectasis with or without elevated sweat chloride 1, modifier of 2008-05-28 no assertion criteria provided literature only

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