7-117642457-C-T

Variant names:

• chr7-117642457-C-T
• rs397508600
• NM_000492.4:c.3737C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PP2 PP3_Moderate PP5_Very_Strong

The NM_000492.4(CFTR):​c.3737C>T​(p.Thr1246Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,613,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T1246T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 U:1
• Conservation: PhyloP100: 5.71
• Publications: 3 publications found

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000492.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 7-117642457-C-T is Pathogenic according to our data. Variant chr7-117642457-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3737C>T	p.Thr1246Ile	missense_variant	Exon 23 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS2	NR_199597.1	n.65+4894G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3737C>T	p.Thr1246Ile	missense_variant	Exon 23 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250992 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461332 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 726974

African (AFR) AF: 0.0000299 AC: 1 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111622

Other (OTH) AF: 0.0000166 AC: 1 AN: 60368

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00000498 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:7 Uncertain:1

Aug 25, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1246 of the CFTR protein (p.Thr1246Ile). This variant is present in population databases (rs397508600, gnomAD 0.0009%). This missense change has been observed in individuals with cystic fibrosis, and intermediate sweat chloride results (PMID: 10923036, 19318346, 20538955, 22678879, 28129813). ClinVar contains an entry for this variant (Variation ID: 53799). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046, 30046002). For these reasons, this variant has been classified as Pathogenic. -

Mar 31, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1246I pathogenic mutation (also known as c.3737C>T), located in coding exon 23 of the CFTR gene, results from a C to T substitution at nucleotide position 3737. The threonine at codon 1246 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported as compound heterozygous with another CFTR alteration in several individuals with cystic fibrosis or CFTR-related disorders (Claustres M et al. Hum. Mutat., 2000;16:143-56; Goubau C et al. Thorax, 2009 Aug;64:683-91; Sermet-Gaudelus I et al. Am. J. Respir. Crit. Care Med., 2010 Oct;182:929-36; Masica DL et al. Hum. Mol. Genet., 2015 Apr;24:1908-17). This position has been shown to be important in binding ATP for chloride channel gating, however, the T1246I alteration was not specifically evaluated (Vergani P et al. Nature, 2005 Feb;433:876-80). This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 03/29/2022). In CFBE cells, this variant showed reduced CFTR function compared to wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077; Han ST et al. JCI Insight, 2018 Jul;3(14):pii 121159). The p.T1246I alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Oct 26, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.3737C>T (p.Thr1246Ile) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding (IPR003439) and AAA+ ATPase (IPR003593) domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250992 control chromosomes (gnomAD). c.3737C>T has been reported in the literature as a compound heterozygous genotype (mostly in trans with the known pathogenic variant p.Phe508del) in multiple individuals affected with Non-Classic Cystic Fibrosis related phenotypes and has been linked to varying clinical consequences; sweat chloride values were reported to be in the intermediate range for at least some of these individuals (example: Claustres_2000, Goubau_2009, El-Seedy_2012, Sosnay_2017_McCague_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal CFTR activity (Han_2018, Raraigh_2018). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified it as VUS (n=2), likely pathogenic (n=2) and pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic, with varying clinical consequences. -

Sep 05, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_SUP, PM2_SUP, PM3_STR, PP3 -

Mar 11, 2023

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information. -

Dec 08, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

CFTR-related disorder Pathogenic:2

Jan 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CFTR c.3737C>T variant is predicted to result in the amino acid substitution p.Thr1246Ile. This variant, along with a second CFTR variant, has been reported in individuals with cystic fibrosis (CF) and cystic fibrosis-related disorders (CF-RD), including congenital bilateral absence of the vas deferens (Table 4, Claustres et al. 2000. PubMed ID: 10923036; Table 1, El-Seedy et al. 2012. PubMed ID: 22678879; Sosnay et al. 2017. PubMed ID: 28129813; CFTR-France database, https://cftr.iurc.montp.inserm.fr/cgi-bin/affiche.cgi?variant=c.3737C%3ET). This variant has also been reported in in the CFTR2 Database in more than 20 patients as a variant of varying clinical consequence and has been reported in the heterozygous state in a study of individuals with COPD or asthma (Supplementary Table 1, Saferali et al. 2022. PubMed ID: 34996830; https://cftr2.org/mutation/general/T1246I/). In vitro experimental studies suggest this variant reduces CFTR function to 10%–20% compared to control (Raraigh et al. 2018. PubMed ID: 29805046; Han et al. 2018. PubMed ID: 30046002). An alternate nucleotide substitution affecting the same amino acid (p.Thr1246Ala), has been reported in an individual with male infertility (Table 2, Li et al. 2022. PubMed ID: 34931337). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD. Taken together, the c.3737C>T (p.Thr1246Ile) variant is interpreted as likely pathogenic. -

Jan 18, 2021

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided Pathogenic:1

Jul 09, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.3737C>T; p.Thr1246Ile variant (rs397508600) is reported in the literature in the compound heterozygous state with a different pathogenic variant in individuals affected with cystic fibrosis, a CFTR-related disorder, or borderline sweat chloride levels with no other significant symptoms (Claustres 2000, El-Seedy 2012, Goubau 2009, Masica 2015, Sermet-Gaudelus 2010, Sosnay 2017). This variant is reported in ClinVar (Variation ID: 53799), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 1246 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses of the variant protein demonstrate 13% of wild-type function, consistent with an intermediate effect (Raraigh 2018). Based on available information, this variant is considered to be likely pathogenic with variable clinical consequences. References: Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-156. El-Seedy A et al. CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes. Hum Mutat. 2012;33(11):1557-1565. Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009;64(8):683-691. Masica DL et al. Missense variants in CFTR nucleotide-binding domains predict quantitative phenotypes associated with cystic fibrosis disease severity. Hum Mol Genet. 2015;24(7):1908-1917. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018;102(6):1062-1077. Sermet-Gaudelus I et al. Clinical phenotype and genotype of children with borderline sweat test and abnormal nasal epithelial chloride transport. Am J Respir Crit Care Med. 2010;182(7):929-936. Sosnay PR et al. Diagnosis of Cystic Fibrosis in Nonscreened Populations. J Pediatr. 2017;181S:S52-S57.e2. References: Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-156. El-Seedy A et al. CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes. Hum Mutat. 2012;33(11):1557-1565. Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009;64(8):683-691. Masica DL et al. Missense variants in CFTR nucleotide-binding domains predict quantitative phenotypes associated with cystic fibrosis disease severity. Hum Mol Genet. 2015;24(7):1908-1917. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018;102(6):1062-1077. Sermet-Gaudelus I et al. Clinical phenotype and genotype of children with borderline sweat test and abnormal nasal epithelial chloride transport. Am J Respir Crit Care Med. 2010;182(7):929-936. Sosnay PR, White TB, Farrell PM, et al. Diagnosis of Cystic Fibrosis in Nonscreened Populations. J Pediatr. 2017;181S:S52-S57.e2. -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Jan 30, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M;.;.
PhyloP100		5.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.0	D;D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		0.98	D;.;.
Vest4		0.96
MutPred		0.68		Loss of disorder (P = 0.0226);.;.;
MVP		1.0
MPC		0.010
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.90
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397508600; hg19: chr7-117282511;