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

gnomAD frequency: 0.00886  dbSNP: rs73715573

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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.
Eurofins Ntd Llc (ga)	RCV000381834	SCV000331080	other	not provided	2016-05-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000381834	SCV000603012	pathogenic	not provided	2023-11-28	criteria provided, single submitter	clinical testing	The 12TG-5T variant in IVS8 is a mild pathogenic variant. When combined with a pathogenic variant on the other chromosome, this variant is not expected to cause classic cystic fibrosis (CF), but may cause a CFTR-related disorder (i.e., an isolated presentation of pancreatitis, congenital bilateral absence of the vas deferens, or mild lung disease) (CFTR2 database). Link to CFTR2 database: http://cftr2.org/
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000309488	SCV000696826	pathogenic	Cystic fibrosis	2022-01-11	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	RCV000309488	SCV001170538	pathogenic	Cystic fibrosis	2023-05-09	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 Center for Human Genetics Tuebingen	RCV000381834	SCV001501415	pathogenic	not provided	2024-06-01	criteria provided, single submitter	clinical testing	CFTR: PM3:Very Strong, PS3:Moderate, PM2:Supporting
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].
Labcorp Genetics (formerly Invitae), Labcorp	RCV000309488	SCV001591258	pathogenic	Cystic fibrosis	2021-12-15	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 gnomAD 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 present on the opposite chromosome (in trans) from a severe pathogenic CFTR variant (PMID: 14685937). When this allele is observed in trans with a severe pathogenic CFTR variant, the penetrance of CFTR-related conditions (CBAVD and/or non-classic CF) is expected to be high (>90%); however, the penetrance of classic CF is low (<20%) (PMID: 14685937, 27447098). Individuals who are homozygous for this variant, or who have this variant in combination with TG[11]T[5], are likely to be asymptomatic (PMID: 34196078). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. 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 variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000309488	SCV001737338	pathogenic	Cystic fibrosis	2021-06-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000381834	SCV001778496	pathogenic	not provided	2023-03-24	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: 22427236, 18507830, 9435322, 23092102, 23554779, 28152038, 28801929, 14685937, 22430190, 7739684, 25033378, 23951356, 7573058, 7506096, 7684646, 1381723, 18306312, 14993601, 12068373, 17394391, 27488005, 28174639, 16778595, 27996019, 25383785, 26500004, 29216686, 26989879, 20560922, 29997923, 28546993, 23416327, 26253411, 17314234, 18616886, 27447098, 22842702, 20977904, 19812525, 15070876, 31180159, 34426522, 34782259)
AiLife Diagnostics, AiLife Diagnostics	RCV000381834	SCV002502403	pathogenic	not provided	2022-03-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000309488	SCV002574050	pathogenic	Cystic fibrosis	2023-09-25	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PS3
3billion	RCV001329936	SCV004013666	pathogenic	Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing	The variant is observed in the gnomAD v2.1.1 ( https://gnomad.broadinstitute.org) dataset at total allele frequency of 0.849%. Intron variant. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10556281, 14685937, 9435322). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 21658649, 25383785, 27469177). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000178713 / PMID: 28152038). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000309488	SCV004807097	likely pathogenic	Cystic fibrosis	2024-03-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000309488	SCV005045492	pathogenic	Cystic fibrosis	2023-05-24	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000309488	SCV005052066	likely pathogenic	Cystic fibrosis	2024-02-01	criteria provided, single submitter	curation
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001329936	SCV005417938	pathogenic	Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing	PS3+PS4+PM3
Suma Genomics	RCV000309488	SCV001847728	uncertain significance	Cystic fibrosis		flagged submission	clinical testing