NM_000492.4(CFTR):c.3737C>T (p.Thr1246Ile) AND Cystic fibrosis

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Oct 8, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000668850.28

Allele description [Variation Report for NM_000492.4(CFTR):c.3737C>T (p.Thr1246Ile)]

NM_000492.4(CFTR):c.3737C>T (p.Thr1246Ile)

Gene:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.3737C>T (p.Thr1246Ile)

HGVS:

NC_000007.14:g.117642457C>T
NG_016465.4:g.181674C>T
NM_000492.4:c.3737C>TMANE SELECT
NP_000483.3:p.Thr1246Ile
NP_000483.3:p.Thr1246Ile
LRG_663t1:c.3737C>T
LRG_663:g.181674C>T
LRG_663p1:p.Thr1246Ile
NC_000007.13:g.117282511C>T
NM_000492.3:c.3737C>T

Protein change:

T1246I

Links:

dbSNP: rs397508600

NCBI 1000 Genomes Browser:

rs397508600

Molecular consequence:

NM_000492.4:c.3737C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

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Chain Y, 40S RIBOSOMAL PROTEIN S24
Chain Y, 40S RIBOSOMAL PROTEIN S24
gi|969813072|pdb|5FLX|Y

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000886147	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (Mar 11, 2023)	unknown	clinical testing	Citation Link,
SCV000919178	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 26, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10923036, 22678879, 19318346, 25489051, 28129813, 29805046, 30046002, 30888834, 15729345 Citation Link,
SCV001425315	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 27, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001590786	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 8, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 10923036, 19318346, 20538955, 22678879, 28129813, 29805046, 30046002, 28492532
SCV002573863	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 5, 2022)	unknown	curation	PubMed (1) [See all records that cite this PMID]
SCV002622539	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 31, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10923036, 15729345, 19318346, 20538955, 25489051, 29805046 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Correlating Cystic Fibrosis Transmembrane Conductance Regulator Function with Clinical Features to Inform Precision Treatment of Cystic Fibrosis.

McCague AF, Raraigh KS, Pellicore MJ, Davis-Marcisak EF, Evans TA, Han ST, Lu Z, Joynt AT, Sharma N, Castellani C, Collaco JM, Corey M, Lewis MH, Penland CM, Rommens JM, Stephenson AL, Sosnay PR, Cutting GR.

Am J Respir Crit Care Med. 2019 May 1;199(9):1116-1126. doi: 10.1164/rccm.201901-0145OC.

PubMed [citation]

PMID:: 30888834
PMCID:: PMC6515867

CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes.

El-Seedy A, Girodon E, Norez C, Pajaud J, Pasquet MC, de Becdelièvre A, Bienvenu T, des Georges M, Cabet F, Lalau G, Bieth E, Blayau M, Becq F, Kitzis A, Fanen P, Ladeveze V.

Hum Mutat. 2012 Nov;33(11):1557-65. doi: 10.1002/humu.22129. Epub 2012 Jul 2.

PubMed [citation]

PMID:: 22678879

See all PubMed Citations (12)

Details of each submission

From Counsyl, SCV000793522.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV000886147.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919178.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Johns Hopkins Genomics, Johns Hopkins University, SCV001425315.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001590786.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046, 30046002). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002573863.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	curation	PubMed (1)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Ambry Genetics, SCV002622539.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000793522	Counsyl	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Aug 25, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000793522

Counsyl

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(Aug 25, 2017)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Last Updated: Oct 26, 2024

Relating variation to medicine