VCV000038850.50 - ClinVar

NM_000492.4(CFTR):c.443T>C (p.Ile148Thr)

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.

(17)

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
Uncertain significance(2); Benign(9); Likely benign(5)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000492.4(CFTR):c.443T>C (p.Ile148Thr)

Variation ID: 38850 Accession: VCV000038850.50

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117531068 (GRCh38) [ NCBI UCSC ] 7: 117171122 (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	Oct 2, 2016	Oct 20, 2024	Apr 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.443T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Ile148Thr	missense
NC_000007.14:g.117531068T>C
NC_000007.13:g.117171122T>C
NG_016465.4:g.70285T>C
LRG_663:g.70285T>C
LRG_663t1:c.443T>C	LRG_663p1:p.Ile148Thr
	P13569:p.Ile148Thr

... more HGVS ... less HGVS

Protein change

I148T

Other names

NM_000492.3(CFTR):c.443T>C(p.Ile148Thr)

Canonical SPDI

NC_000007.14:117531067:T:C

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.

0.00140 (C)

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

1000 Genomes Project 30x 0.00109

1000 Genomes Project 0.00140

The Genome Aggregation Database (gnomAD), exomes 0.00178

Exome Aggregation Consortium (ExAC) 0.00187

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054

The Genome Aggregation Database (gnomAD) 0.00083

Trans-Omics for Precision Medicine (TOPMed) 0.00101

Links

ClinGen: CA146708 Genetic Testing Registry (GTR): GTR000257096 UniProtKB: P13569#VAR_000128 dbSNP: rs35516286 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	3832	5210

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.
Cystic fibrosis	Conflicting interpretations of pathogenicity (10)	criteria provided, conflicting classifications	Apr 30, 2024	RCV000047138.36
not specified	Benign (3)	criteria provided, multiple submitters, no conflicts	Dec 24, 2019	RCV000079009.26
CFTR-related disorder	Uncertain significance (1)	criteria provided, single submitter	Mar 6, 2018	RCV001095251.13
not provided	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Nov 15, 2023	RCV001705619.25

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000304500.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Likely benign (Feb 23, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001830562.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Comment: In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the … (more) In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 1284534, 23974870, 9305991, 12394343, 10653141, 11484207, 22658665, 22975760, 20021716, 15287992, 26990548, 7517268, 15017334, 18456578, 18685558, 16822950, 11242048, 19491324, 15371902) (less)
Benign (Aug 06, 2012)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110878.8 First in ClinVar: Jan 17, 2014 Last updated: Oct 02, 2016	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: 1 Sex: mixed
Benign (Jun 25, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001425332.1 First in ClinVar: Aug 03, 2020 Last updated: Aug 03, 2020
Uncertain significance (Sep 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Cystic fibrosis Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002574072.1 First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022	Comment: This variant was identified in 2 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a … (more) This variant was identified in 2 unrelated patients 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: PM5, PP4, BS2, BS3, BP2 (less) Number of individuals with the variant: 2
Benign (Dec 24, 2019)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001469505.2 First in ClinVar: Jan 26, 2021 Last updated: Dec 31, 2022	Publications: PubMed (7) PubMed: 11242048‚ 16822950‚ 15017334‚ 15287992‚ 12394343‚ 23670503‚ 12172395
Likely benign (Apr 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Cystic fibrosis Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803630.2 First in ClinVar: Aug 04, 2018 Last updated: May 07, 2024	Comment: This variant is interpreted as a likely benign, for Cystic fibrosis, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS2 => Observed in … (more) This variant is interpreted as a likely benign, for Cystic fibrosis, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:12394343). (less)
Likely benign (Oct 01, 2023)	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: SCV004158944.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: CFTR: PM5, BS2 Number of individuals with the variant: 3
Likely benign (Apr 14, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000790922.1 First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018	Publications: PubMed (8) PubMed: 18456578‚ 15371902‚ 12394343‚ 11242048‚ 23974870‚ 9305991‚ 19491324‚ 16822950
Benign (Jan 29, 2018)	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017)) Method: curation	cystic fibrosis Affected status: no, yes Allele origin: germline	CFTR-France Accession: SCV001169190.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Publications: PubMed (1) PubMed: 28603918 Comment: the variant does not result in CFTR-RD neither Observation 1: Observation 2:
Uncertain significance (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	CFTR-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000466503.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Likely benign (Jun 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001737321.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Sex: mixed
Benign (Aug 22, 2023)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Mendelics Accession: SCV000886144.3 First in ClinVar: Aug 04, 2018 Last updated: Aug 25, 2023
Benign (Nov 15, 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: SCV000603005.5 First in ClinVar: Oct 02, 2016 Last updated: Feb 20, 2024
Benign (Jan 30, 2024)	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: SCV000075151.11 First in ClinVar: Jul 03, 2013 Last updated: Feb 28, 2024
Benign (Mar 13, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001184227.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (Aug 06, 2019)	no assertion criteria provided Method: clinical testing	Cystic Fibrosis Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001453949.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
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Comment:

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 1284534, 23974870, 9305991, 12394343, 10653141, 11484207, 22658665, 22975760, 20021716, 15287992, 26990548, 7517268, 15017334, 18456578, 18685558, 16822950, 11242048, 19491324, 15371902)

Comment:

This variant was identified in 2 unrelated patients 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: PM5, PP4, BS2, BS3, BP2

Comment:

This variant is interpreted as a likely benign, for Cystic fibrosis, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:12394343).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.	Sosnay PR	Nature genetics	2013	PMID: 23974870
Diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator gene in patients suspected of having mild or atypical cystic fibrosis.	Dal'Maso VB	Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia	2013	PMID: 23670503
Mutation-specific potency and efficacy of cystic fibrosis transmembrane conductance regulator chloride channel potentiators.	Caputo A	The Journal of pharmacology and experimental therapeutics	2009	PMID: 19491324
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
Abnormal regulatory interactions of I148T-CFTR and the epithelial Na+ channel in Xenopus oocytes.	Suaud L	American journal of physiology. Cell physiology	2007	PMID: 16822950
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
Are p.I148T, p.R74W and p.D1270N cystic fibrosis causing mutations?	Claustres M	BMC medical genetics	2004	PMID: 15287992
Frequency of the cystic fibrosis 3199del6 mutation in individuals heterozygous for I148T.	Buller A	Genetics in medicine : official journal of the American College of Medical Genetics	2004	PMID: 15017334
The I148T CFTR allele occurs on multiple haplotypes: a complex allele is associated with cystic fibrosis.	Rohlfs EM	Genetics in medicine : official journal of the American College of Medical Genetics	2002	PMID: 12394343
Cystic fibrosis screening using the College panel: platform comparison and lessons learned from the first 20,000 samples.	Strom CM	Genetics in medicine : official journal of the American College of Medical Genetics	2002	PMID: 12172395
Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis.	Choi JY	Nature	2001	PMID: 11242048
Disease-associated mutations in cytoplasmic loops 1 and 2 of cystic fibrosis transmembrane conductance regulator impede processing or opening of the channel.	Seibert FS	Biochemistry	1997	PMID: 9305991
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR	-	-	-	-
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Text-mined citations for rs35516286 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.443T>C (p.Ile148Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs35516286 ...