VCV000242535.61 - ClinVar

NM_000492.3(CFTR):c.1210-12T[5]

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(24)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(13); Likely pathogenic(1); Uncertain significance(1); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Haplotype

NM_000492.3(CFTR):c.[350G>A;1210-12[5]]

Identifiers

NM_000492.3(CFTR):c.1210-12T[5]

Variation ID: 242535 Accession: VCV000242535.61

Type and length

Deletion, 2 bp

Location

Cytogenetic: 7q31.2 7: 117548629-117548630 (GRCh38) [ NCBI UCSC ] 7: 117188683 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 29, 2016	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.1210-7_1210-6del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_000492.3:c.1210-12[5]
NM_000492.3:c.1210-7_1210-6del
NM_000492.3:c.1210-7_1210-6delTT
NC_000007.14:g.117548629T[5]
NC_000007.13:g.117188683T[5]
NG_016465.4:g.87846T[5]
NG_016465.4:g.87851_87852del
LRG_663:g.87851_87852del
LRG_663t1:c.1210-12T[5]

... more HGVS ... less HGVS

Protein change

Other names

5T/7T/9T

Canonical SPDI

NC_000007.14:117548628:TTTTTTT:TTTTT

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.02316 (TTTTT)

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

Genetic Testing Registry (GTR): GTR000074114 OMIM: 602421.0086 dbSNP: rs1805177 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CFTR		-	-	GRCh38 GRCh37	3825	5200
CFTR-AS1	-	-	-	GRCh38	-	512

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	no classifications from unflagged records (2)	no classifications from unflagged records	Apr 8, 2024	RCV000155619.30
Bronchiectasis with or without elevated sweat chloride 1, modifier of	risk factor (1)	no assertion criteria provided	May 28, 2008	RCV000007610.14
Cystic fibrosis	Conflicting interpretations of pathogenicity (7)	criteria provided, conflicting classifications	Sep 4, 2023	RCV000173692.31
Congenital bilateral aplasia of vas deferens from CFTR mutation	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 22, 2021	RCV000007609.27
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000405075.40
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Feb 14, 2019	RCV001010359.11
CFTR-related disorder Cystic fibrosis	Pathogenic (1)	criteria provided, single submitter	Jan 29, 2018	RCV001009378.10
Obstructive azoospermia	Likely pathogenic (1)	criteria provided, single submitter	Aug 23, 2021	RCV001706280.11
Hereditary pancreatitis	Pathogenic (1)	criteria provided, single submitter	Feb 1, 2022	RCV002243923.9
Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Hereditary pancreatitis	not provided (1)	no classification provided	-	RCV003330602.2
Congenital bilateral absence of vas deferens	not provided (1)	no classification provided	-	RCV003483594.1
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	CFTR-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000466508.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Pathogenic (Jul 14, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329660.3 First in ClinVar: Dec 06, 2016 Last updated: Dec 19, 2017	Comment: 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 … (more) 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. (less)
Pathogenic (Mar 17, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331631.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR Number of individuals with the variant: 177 Sex: mixed
Pathogenic (Jan 29, 2018)	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017)) Method: curation	cystic fibrosis CFTR-related disorders Affected status: yes Allele origin: germline	CFTR-France Accession: SCV001169231.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Publications: PubMed (1) PubMed: 28603918 Comment: when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Pathogenic (Oct 18, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193799.1 First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020	Publications: PubMed (1) PubMed: 23974870 Comment: 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 … (more) 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. (less)
Pathogenic (Nov 05, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: unknown	Mendelics Accession: SCV000886265.2 First in ClinVar: Jul 20, 2018 Last updated: Dec 11, 2022
Pathogenic (Feb 14, 2019)	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (3/2017)) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001170545.3 First in ClinVar: Mar 16, 2020 Last updated: Mar 04, 2023	Comment: 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 … (more) 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). (less) Number of individuals with the variant: 1
Pathogenic (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000693251.24 First in ClinVar: Dec 19, 2017 Last updated: Oct 20, 2024	Comment: CFTR: PM3:Very Strong, PS3:Moderate, PM2:Supporting, BP4 Number of individuals with the variant: 14
Pathogenic (Nov 04, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Congenital bilateral aplasia of vas deferens from CFTR mutation Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001362614.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (21) PubMed: 19092437‚ 11354633‚ 7684646‚ 9435322‚ 14685937‚ 17329263‚ 15905293‚ 17489851‚ 11729110‚ 20691141‚ 18456578‚ 21520337‚ 14993601‚ 16840743‚ 18685558‚ 23810505‚ 22842702‚ 16778595‚ 25251442‚ 10668931‚ 18567645 Comment: 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 … (more) 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. (less)
Pathogenic (Jul 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital bilateral aplasia of vas deferens from CFTR mutation Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001822040.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Sex: mixed
Likely pathogenic (Aug 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Obstructive azoospermia Affected status: yes Allele origin: germline	Institute of Reproductive Genetics, University of Münster Accession: SCV001911515.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Number of individuals with the variant: 4
Pathogenic (Dec 12, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001587195.2 First in ClinVar: May 10, 2021 Last updated: May 16, 2022	Publications: PubMed (10) PubMed: 14685937‚ 27447098‚ 16778595‚ 21520337‚ 34196078‚ 7691356‚ 7684641‚ 10556281‚ 21658649‚ 9435322 Comment: This sequence change, also referred to as 5T;TG11 or TG11-5T in the literature, consists of 11 TG and 5 T sequence repeats on the same … (more) This sequence change, also referred to as 5T;TG11 or TG11-5T in the literature, consists of 11 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[11]T[5] allele has been observed in males with congenital bilateral absence of the vas deferens (CBAVD), with a penetrance of ~32%, when present on the opposite chromosome (in trans) from a severe pathogenic CFTR variant (PMID: 14685937). The TG[11]T[5] allele is not expected to cause cystic fibrosis in either males or females when in trans with a severe pathogenic CFTR variant (PMID: 14685937, 27447098), although individuals with borderline sweat chloride results and/or mild respiratory disease have been reported (PMID: 16778595). The combination of the TG[11]T[5] allele in trans with another 5T allele (TG11-13), is unlikely to be associated with CFTR-related symptoms (PMID: 21520337, 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) and partial loss of function. 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). In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the CFTR gene, it has been classified as Pathogenic (low penetrance). (less)
Pathogenic (Feb 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512245.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: ACMG classification criteria: PS3 supporting, PS4 strong, PM3 very strong Geographic origin: Brazil
Pathogenic (Dec 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV002818248.1 First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023
Pathogenic (Nov 24, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002047826.7 First in ClinVar: Jan 08, 2022 Last updated: Feb 20, 2024	Comment: The 11TG-5T variant in IVS8 is the mildest type of 5T variant. When combined with a pathogenic variant on the other chromosome, this variant is … (more) The 11TG-5T variant in IVS8 is the mildest type of 5T 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/ (less)
Uncertain significance (Sep 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004812068.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Clinical Features: Chronic pancreatitis (present) , Atresia of the external auditory canal (present) Sex: male
risk factor (May 28, 2008)	no assertion criteria provided Method: literature only	BRONCHIECTASIS WITH OR WITHOUT ELEVATED SWEAT CHLORIDE 1, MODIFIER OF Affected status: not provided Allele origin: germline	OMIM Accession: SCV000053489.3 First in ClinVar: Apr 04, 2013 Last updated: Aug 14, 2021	Publications: PubMed (8) PubMed: 7573058‚ 7684646‚ 7506096‚ 8556303‚ 2344617‚ 14685937‚ 14993601‚ 18507830 Comment on evidence: Zielenski et al. (1995) estimated that CBAVD (277180) is associated with the 5T variant at the 3-prime end of intron 8 of the CFTR gene … (more) Zielenski et al. (1995) estimated that CBAVD (277180) is associated with the 5T variant at the 3-prime end of intron 8 of the CFTR gene with a penetrance of 0.60 in males. Chu et al. (1993) noted varied lengths of a thymidine (T)-tract (5, 7, or 9T) in front of the splice-acceptor site of intron 8. The length appeared to correlate with the efficiency of exon 9 splicing, with the 5T variant that is present in 5% of the CFTR alleles among the Caucasian population producing almost exclusively (95%) exon 9-minus mRNA. The effect of this T-tract polymorphism in CFTR gene expression was also documented by its relationship with the CF mutation R117H (602421.0005): while R117H (5T) is found in typical CF patients with pancreatic sufficiency, R117H (7T) is associated with CBAVD (Kiesewetter et al., 1993). Costes et al. (1995) studied the CFTR gene in 45 azoospermic individuals with isolated CBAVD. They detected a CFTR gene defect in 86% of chromosomes from these subjects. In addition to identifying 9 novel CFTR gene mutations, they found that 84% of men with CBAVD who were heterozygous for a CF mutation carried the intron 8 polypyrimidine 5T CFTR allele on 1 chromosome. De Meeus et al. (1998) found linkage disequilibrium between the 5T allele and the val allele of the met470-to-val polymorphism (602421.0023). Groman et al. (2004) demonstrated that the number of TG repeats adjacent to 5T influences disease penetrance. They determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. They found that those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats. Thus, determination of TG repeat number will allows for more accurate prediction of benign versus pathogenic 5T alleles. The TG repeat located at the splice acceptor site of exon 9 of the CFTR gene is an example of a variable dinucleotide repeat that affects splicing. Higher repeat numbers result in reduced exon 9 splicing efficiency and, in some instances, the reduction in full-length transcript is sufficient to cause male infertility due to congenital bilateral absence of the vas deferens or nonclassic cystic fibrosis. Using a CFTR minigene system, Hefferon et al. (2004) studied TG tract variation and observed the same correlation between dinucleotide repeat number and exon 9 splicing efficiency seen in vivo. Replacement of the TG dinucleotide tract in the minigene with random sequence abolished splicing of exon 9. Replacements of the TG tract with sequences that can self-basepair suggested that the formation of an RNA secondary structure was associated with efficient splicing. However, splicing efficiency was inversely correlated with the predicted thermodynamic stability of such structures, demonstrating that intermediate stability was optimal. Finally, substitution of TA repeats of differing lengths confirmed that stability of the RNA secondary structure, not sequence content, correlated with splicing efficiency. Taken together, these data indicated that dinucleotide repeats can form secondary structures that have variable effects on RNA splicing efficiency and clinical phenotype. In a 66-year-old woman and an unrelated 67-year-old man with idiopathic bronchiectasis (BESC1; 211400), who were heterozygous for the 5T CFTR variant, Fajac et al. (2008) also identified heterozygosity for a missense mutation in the SCNN1B gene (600760.0015). The woman had a borderline elevated sweat chloride, normal nasal potential difference (PD), and FEV1 that was 77% of predicted. The man had normal sweat chloride and nasal PD, and FEV1 that was 80% of predicted. Fajac et al. (2008) concluded that variants in SCNN1B may be deleterious for sodium channel function and lead to bronchiectasis, especially in patients who also carry a mutation in the CFTR gene. (less)
Pathogenic (May 28, 2008)	no assertion criteria provided Method: literature only	VAS DEFERENS, CONGENITAL BILATERAL ABSENCE OF Affected status: not provided Allele origin: germline	OMIM Accession: SCV000027810.3 First in ClinVar: Apr 04, 2013 Last updated: Aug 14, 2021	Publications: PubMed (8) PubMed: 7573058‚ 7684646‚ 7506096‚ 8556303‚ 2344617‚ 14685937‚ 14993601‚ 18507830 Comment on evidence: Zielenski et al. (1995) estimated that CBAVD (277180) is associated with the 5T variant at the 3-prime end of intron 8 of the CFTR gene … (more) Zielenski et al. (1995) estimated that CBAVD (277180) is associated with the 5T variant at the 3-prime end of intron 8 of the CFTR gene with a penetrance of 0.60 in males. Chu et al. (1993) noted varied lengths of a thymidine (T)-tract (5, 7, or 9T) in front of the splice-acceptor site of intron 8. The length appeared to correlate with the efficiency of exon 9 splicing, with the 5T variant that is present in 5% of the CFTR alleles among the Caucasian population producing almost exclusively (95%) exon 9-minus mRNA. The effect of this T-tract polymorphism in CFTR gene expression was also documented by its relationship with the CF mutation R117H (602421.0005): while R117H (5T) is found in typical CF patients with pancreatic sufficiency, R117H (7T) is associated with CBAVD (Kiesewetter et al., 1993). Costes et al. (1995) studied the CFTR gene in 45 azoospermic individuals with isolated CBAVD. They detected a CFTR gene defect in 86% of chromosomes from these subjects. In addition to identifying 9 novel CFTR gene mutations, they found that 84% of men with CBAVD who were heterozygous for a CF mutation carried the intron 8 polypyrimidine 5T CFTR allele on 1 chromosome. De Meeus et al. (1998) found linkage disequilibrium between the 5T allele and the val allele of the met470-to-val polymorphism (602421.0023). Groman et al. (2004) demonstrated that the number of TG repeats adjacent to 5T influences disease penetrance. They determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. They found that those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats. Thus, determination of TG repeat number will allows for more accurate prediction of benign versus pathogenic 5T alleles. The TG repeat located at the splice acceptor site of exon 9 of the CFTR gene is an example of a variable dinucleotide repeat that affects splicing. Higher repeat numbers result in reduced exon 9 splicing efficiency and, in some instances, the reduction in full-length transcript is sufficient to cause male infertility due to congenital bilateral absence of the vas deferens or nonclassic cystic fibrosis. Using a CFTR minigene system, Hefferon et al. (2004) studied TG tract variation and observed the same correlation between dinucleotide repeat number and exon 9 splicing efficiency seen in vivo. Replacement of the TG dinucleotide tract in the minigene with random sequence abolished splicing of exon 9. Replacements of the TG tract with sequences that can self-basepair suggested that the formation of an RNA secondary structure was associated with efficient splicing. However, splicing efficiency was inversely correlated with the predicted thermodynamic stability of such structures, demonstrating that intermediate stability was optimal. Finally, substitution of TA repeats of differing lengths confirmed that stability of the RNA secondary structure, not sequence content, correlated with splicing efficiency. Taken together, these data indicated that dinucleotide repeats can form secondary structures that have variable effects on RNA splicing efficiency and clinical phenotype. In a 66-year-old woman and an unrelated 67-year-old man with idiopathic bronchiectasis (BESC1; 211400), who were heterozygous for the 5T CFTR variant, Fajac et al. (2008) also identified heterozygosity for a missense mutation in the SCNN1B gene (600760.0015). The woman had a borderline elevated sweat chloride, normal nasal potential difference (PD), and FEV1 that was 77% of predicted. The man had normal sweat chloride and nasal PD, and FEV1 that was 80% of predicted. Fajac et al. (2008) concluded that variants in SCNN1B may be deleterious for sodium channel function and lead to bronchiectasis, especially in patients who also carry a mutation in the CFTR gene. (less)
not provided (-)	no classification provided Method: literature only	Cystic fibrosis Affected status: unknown Allele origin: unknown	GeneReviews Accession: SCV001652691.2 First in ClinVar: May 23, 2021 Last updated: Oct 01, 2022	Publications: PubMed (5) PubMed: 20301428‚ 15371902‚ 11491164‚ 7506096‚ 10103316 BookShelf: NBK1250 BookShelf: NBK1250 Comment: The severity of lung disease in individuals heterozygous or homozygous for p.Arg117His depends on the presence of a variation in the poly T tract of … (more) The severity of lung disease in individuals heterozygous or homozygous for p.Arg117His depends on the presence of a variation in the poly T tract of intron 9, c.1210-12T[5_9] [Massie et al 2001]. Individuals with a CF-causing variant plus the 5T variant in cis with p.Arg117His usually develop the lung disease of CF, but those individuals with p.Arg117His and the 7T variant or the 9T variant have a highly variable phenotype that can range from no symptoms to mild lung disease [Kiesewetter et al 1993, Chmiel et al 1999]. (less)
not provided (-)	no classification provided Method: phenotyping only	Cystic fibrosis Congenital bilateral aplasia of vas deferens from CFTR mutation Hereditary pancreatitis Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV004037539.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023	Comment: Variant classified as Pathogenic and reported on 07-26-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more) Variant classified as Pathogenic and reported on 07-26-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Asthma (present) , Abnormal pattern of respiration (present) , Immunodeficiency (present) , Recurrent infections (present) Indication for testing: Diagnostic Age: 30-39 years Sex: male Method: Gene Panel Sequencing Testing laboratory: Invitae Date variant was reported to submitter: 2017-07-26 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: phenotyping only	Congenital bilateral absence of vas deferens Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV004228523.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Comment: Variant interpreted as Pathogenic and reported on 07-07-2016 by Lab LabCorp. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Pathogenic and reported on 07-07-2016 by Lab LabCorp. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Myopia (present) , Abnormal intestine morphology (present) , Abnormality of the pancreas (present) Age: 50-59 years Sex: male Method: Gene Panel Sequencing Testing laboratory: Laboratory Corporation of America Holdings Date variant was reported to submitter: 2016-07-07 Testing laboratory interpretation: Pathogenic
Uncertain significance (Jan 14, 2016)	Flagged submission flagged submission (LMM Criteria) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000205327.4 First in ClinVar: Jan 31, 2015 Last updated: May 29, 2016	Publications: PubMed (10) PubMed: 14685937‚ 7506096‚ 11069835‚ 17314234‚ 16020494‚ 7739684‚ 1381723‚ 7684646‚ 16263954‚ 9435322 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 2
Pathogenic (Feb 08, 2020)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV001984010 appears to (...more) Source: NCBI	not specified Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV001984010.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 Comment: The c.1210-12T[5] variant also referred to as the 5T allele occurs in the poly T tract in intron 8 of the CFTR gene. This variant … (more) The c.1210-12T[5] variant also referred to as the 5T allele occurs in the poly T tract in intron 8 of the CFTR gene. This variant acts as a disease susceptibility variant with reduced penetrance and variable expressivity1. Specifically the 5T 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 fibrosis12. However the penetrance of the 5T allele 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 5T are associated with a greater susceptibility to disease than when in cis with a smaller TG repeat size (TG11)134. RNA studies demonstrate that the c.1210-12T[5] variant affects mRNA splicing56. The c.1210-12T[5] variant has been observed in 7% (1260/17968 25 homozygotes) and 2.9% (3015/103332 13 homozygotes) African and European Non Finnish alleles respectively. Therefore based on the information available we interpret c.1210-12T[5] as a pathogenic variant with reduced penetrance and variable expressivity. 1. Ong T Marshall S. Karczeski B. et al. Cystic Fibrosis and Congenital Absence of the Vas Deferens. 2001 Mar 26 [Updated 2017 Feb 2]. In: Adam MP Ardinger HH Pagon RA et al. editors. GeneReviews® [Internet]. Seattle (WA): University of Washington Seattle 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1250/ 2. Chillón M. Casals T. et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med. Jun 1332(22):1475-80. (1995) 3. Cuppens H Lin W Jaspers M et al. Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation. J Clin Invest.101(2):487–496. (1998) 4 Groman JD Hefferon TW Casals T et al. Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign. Am J Hum Genet.74(1):176–179.(2004) 5 Chu CS Trapnell BC Curristin SM Cutting GR Crystal RG. Extensive posttranscriptional deletion of the coding sequences for part of nucleotide-binding fold 1 in respiratory epithelial mRNA transcripts of the cystic fibrosis transmembrane conductance regulator gene is not associated with the clinical manifestations of cystic fibrosis. J Clin Invest. 90(3):785–790. (1992) 6. Hefferon TW Broackes-Carter FC Harris A Cutting GR. Atypical 5' splice sites cause CFTR exon 9 to be vulnerable to skipping. Am J Hum Genet. 71(2):294–303. (2002) (less)
Uncertain significance (Mar 26, 2024)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Cystic fibrosis Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004807015.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
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Comment:

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.

Comment:

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.

Comment:

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).

Comment:

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.

Comment:

This sequence change, also referred to as 5T;TG11 or TG11-5T in the literature, consists of 11 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[11]T[5] allele has been observed in males with congenital bilateral absence of the vas deferens (CBAVD), with a penetrance of ~32%, when present on the opposite chromosome (in trans) from a severe pathogenic CFTR variant (PMID: 14685937). The TG[11]T[5] allele is not expected to cause cystic fibrosis in either males or females when in trans with a severe pathogenic CFTR variant (PMID: 14685937, 27447098), although individuals with borderline sweat chloride results and/or mild respiratory disease have been reported (PMID: 16778595). The combination of the TG[11]T[5] allele in trans with another 5T allele (TG11-13), is unlikely to be associated with CFTR-related symptoms (PMID: 21520337, 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) and partial loss of function. 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). In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the CFTR gene, it has been classified as Pathogenic (low penetrance).

Comment:

The 11TG-5T variant in IVS8 is the mildest type of 5T 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/

Comment:

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.

Comment:

The severity of lung disease in individuals heterozygous or homozygous for p.Arg117His depends on the presence of a variation in the poly T tract of intron 9, c.1210-12T[5_9] [Massie et al 2001]. Individuals with a CF-causing variant plus the 5T variant in cis with p.Arg117His usually develop the lung disease of CF, but those individuals with p.Arg117His and the 7T variant or the 9T variant have a highly variable phenotype that can range from no symptoms to mild lung disease [Kiesewetter et al 1993, Chmiel et al 1999].

Comment:

Variant classified as Pathogenic and reported on 07-26-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Comment:

Variant interpreted as Pathogenic and reported on 07-07-2016 by Lab LabCorp. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Elucidating clinical phenotypic variability associated with the polyT tract and TG repeats in CFTR.	Nykamp K	Human mutation	2021	PMID: 34196078
Phenotypes of California CF Newborn Screen-Positive Children with CFTR 5T Allele by TG Repeat Length.	Salinas DB	Genetic testing and molecular biomarkers	2016	PMID: 27447098
Evaluating Adults With Idiopathic Pancreatitis for Genetic Predisposition: Higher Prevalence of Abnormal Results With Use of Complete Gene Sequencing.	Ballard DD	Pancreas	2015	PMID: 25251442
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.	Sosnay PR	Nature genetics	2013	PMID: 23974870
Novel CFTR variants identified during the first 3 years of cystic fibrosis newborn screening in California.	Prach L	The Journal of molecular diagnostics : JMD	2013	PMID: 23810505
The CFTR polymorphisms poly-T, TG-repeats and M470V in Chinese males with congenital bilateral absence of the vas deferens.	Ni WH	Asian journal of andrology	2012	PMID: 22842702
Recommendations for the classification of diseases as CFTR-related disorders.	Bombieri C	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2011	PMID: 21658649
Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens.	Steiner B	Human mutation	2011	PMID: 21520337
Clinical hallmarks and genetic polymorphisms in the CFTR gene contribute to the disclosure of the A1006E mutation.	Tomaiuolo AC	Clinical and investigative medicine. Medecine clinique et experimentale	2010	PMID: 20691141
Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders--updated European recommendations.	Dequeker E	European journal of human genetics : EJHG	2009	PMID: 18685558
Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders.	Moskowitz SM	Genetics in medicine : official journal of the American College of Medical Genetics	2008	PMID: 19092437
Genetic investigations of CFTR mutations in congenital absence of vas deferens, uterus, and vagina as a cause of infertility.	Radpour R	Journal of andrology	2008	PMID: 18567645
Could a defective epithelial sodium channel lead to bronchiectasis.	Fajac I	Respiratory research	2008	PMID: 18507830
Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice.	Castellani C	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2008	PMID: 18456578
Contribution of the CFTR gene, the pancreatic secretory trypsin inhibitor gene (SPINK1) and the cationic trypsinogen gene (PRSS1) to the etiology of recurrent pancreatitis.	Tzetis M	Clinical genetics	2007	PMID: 17489851
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.	Ratbi I	Human reproduction (Oxford, England)	2007	PMID: 17329263
Molecular study of (TG)m(T)n polymorphisms in Iranian males with congenital bilateral absence of the vas deferens.	Radpour R	Journal of andrology	2007	PMID: 17314234
Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials.	Wilschanski M	American journal of respiratory and critical care medicine	2006	PMID: 16840743
CFTR 5T variant has a low penetrance in females that is partially attributable to its haplotype.	Sun W	Genetics in medicine : official journal of the American College of Medical Genetics	2006	PMID: 16778595
Late CF caused by homozygous IVS8-5T CFTR polymorphism.	Cottin V	Thorax	2005	PMID: 16263954
Direct molecular haplotyping of the IVS-8 poly(TG) and polyT repeat tracts in the cystic fibrosis gene by melting curve analysis of hybridization probes.	Millson A	Clinical chemistry	2005	PMID: 16020494
Mutation spectrum of the CFTR gene in Taiwanese patients with congenital bilateral absence of the vas deferens.	Wu CC	Human reproduction (Oxford, England)	2005	PMID: 15905293
Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel.	Watson MS	Genetics in medicine : official journal of the American College of Medical Genetics	2004	PMID: 15371902
A variable dinucleotide repeat in the CFTR gene contributes to phenotype diversity by forming RNA secondary structures that alter splicing.	Hefferon TW	Proceedings of the National Academy of Sciences of the United States of America	2004	PMID: 14993601
Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign.	Groman JD	American journal of human genetics	2004	PMID: 14685937
Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutations.	Noone PG	Gastroenterology	2001	PMID: 11729110
Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C.	Massie RJ	The European respiratory journal	2001	PMID: 11491164
CFTR gene mutations--including three novel nucleotide substitutions--and haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease.	Tzetis M	Human genetics	2001	PMID: 11354633
Lung disease associated with the IVS8 5T allele of the CFTR gene.	Noone PG	American journal of respiratory and critical care medicine	2000	PMID: 11069835
Polyvariant mutant CFTR genes in patients with chronic pancreatitis.	Arduino C	Clinical genetics	1999	PMID: 10668931
Functional analysis of cis-acting elements regulating the alternative splicing of human CFTR exon 9.	Niksic M	Human molecular genetics	1999	PMID: 10556281
Pitfall in the use of genotype analysis as the sole diagnostic criterion for cystic fibrosis.	Chmiel JF	Pediatrics	1999	PMID: 10103316
Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation.	Cuppens H	The Journal of clinical investigation	1998	PMID: 9435322
Frequent occurrence of the CFTR intron 8 (TG)n 5T allele in men with congenital bilateral absence of the vas deferens.	Costes B	European journal of human genetics : EJHG	1995	PMID: 8556303
Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens.	Chillón M	The New England journal of medicine	1995	PMID: 7739684
CFTR gene variant for patients with congenital absence of vas deferens.	Zielenski J	American journal of human genetics	1995	PMID: 7573058
Cystic fibrosis transmembrane conductance regulator splice variants are not conserved and fail to produce chloride channels.	Delaney SJ	Nature genetics	1993	PMID: 7691356
Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA.	Chu CS	Nature genetics	1993	PMID: 7684646
Expression of an abundant alternatively spliced form of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is not associated with a cAMP-activated chloride conductance.	Strong TV	Human molecular genetics	1993	PMID: 7684641
A mutation in CFTR produces different phenotypes depending on chromosomal background.	Kiesewetter S	Nature genetics	1993	PMID: 7506096
Extensive posttranscriptional deletion of the coding sequences for part of nucleotide-binding fold 1 in respiratory epithelial mRNA transcripts of the cystic fibrosis transmembrane conductance regulator gene is not associated with the clinical manifestations of cystic fibrosis.	Chu CS	The Journal of clinical investigation	1992	PMID: 1381723
Multiple mutations in highly conserved residues are found in mildly affected cystic fibrosis patients.	Dean M	Cell	1990	PMID: 2344617
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR	-	-	-	-
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Text-mined citations for rs1805177 ...

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Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000492.3(CFTR):c.1210-12T[5]

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Citations for germline classification of this variant

Text-mined citations for rs1805177 ...