VCV000053167.26 - ClinVar

NM_000492.4(CFTR):c.1021T>C (p.Ser341Pro)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Pathogenic

for Cystic fibrosis

Classification is based on the expert panel submission

Mar 2017 by CFTR2

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000492.4(CFTR):c.1021T>C (p.Ser341Pro)

Variation ID: 53167 Accession: VCV000053167.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117540251 (GRCh38) [ NCBI UCSC ] 7: 117180305 (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	Jan 6, 2018	Apr 13, 2025	Mar 17, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.1021T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Ser341Pro	missense
NC_000007.14:g.117540251T>C
NC_000007.13:g.117180305T>C
NG_016465.4:g.79468T>C
LRG_663:g.79468T>C
LRG_663t1:c.1021T>C	LRG_663p1:p.Ser341Pro

... more HGVS ... less HGVS

Protein change

S341P

Other names

Canonical SPDI

NC_000007.14:117540250: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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA328077 dbSNP: rs397508144 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		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	4081	5549

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	Pathogenic (7)	reviewed by expert panel	Mar 17, 2017	RCV000056338.19
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 22, 2022	RCV000724655.12
Bronchiectasis with or without elevated sweat chloride 1 Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Hereditary pancreatitis	Pathogenic (1)	criteria provided, single submitter	Apr 7, 2024	RCV002496707.2
Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis	Pathogenic (1)	criteria provided, single submitter	-	RCV001004248.2
Bronchiectasis with or without elevated sweat chloride 1	Pathogenic (1)	criteria provided, single submitter	Sep 7, 2023	RCV003473441.1

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.
Pathogenic (Mar 17, 2017) C Contributing to aggregate classification	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013)) Method: research	Cystic fibrosis Affected status: yes Allele origin: germline	CFTR2 Study: CFTR2 Accession: SCV000071526.4 First in ClinVar: Oct 18, 2013 Last updated: Jan 06, 2018	Other databases https://cftr2.org https://cftr2.org

Pathogenic (Dec 20, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002525769.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022	Publications: PubMed (4) PubMed: 23891399‚ 23974870‚ 30046002‚ 31036917 Comment: PP3, PM2, PM3_strong, PS3

Likely pathogenic (Jul 22, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003826257.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024

Pathogenic (Apr 19, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002678835.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 23891399‚ 23974870 Comment: The p.S341P pathogenic mutation (also known as c.1021T>C), located in coding exon 8 of the CFTR gene, results from a T to C substitution at … (more) The p.S341P pathogenic mutation (also known as c.1021T>C), located in coding exon 8 of the CFTR gene, results from a T to C substitution at nucleotide position 1021. The serine at codon 341 is replaced by proline, an amino acid with similar properties. In a cohort of individuals with cystic fibrosis, this mutation was identified in 377 individuals and is associated with elevated sweat chloride levels, and a higher rate of Pseudomonas infection (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition, analysis in FRT studies demonstrated reduced CFTR protein levels and undetectable chloride conductance (Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)

Pathogenic (Oct 10, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000700810.3 First in ClinVar: Jan 06, 2018 Last updated: Apr 13, 2025	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 Zygosity: Single Heterozygote Sex: mixed

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001163124.1 First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020

Pathogenic (Mar 22, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002500580.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (3) PubMed: 23974870‚ 23891399‚ 30888834 Comment: Variant summary: CFTR c.1021T>C (p.Ser341Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more) Variant summary: CFTR c.1021T>C (p.Ser341Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251226 control chromosomes (gnomAD). c.1021T>C has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Sosnay_2013, McCague_2019, CFTR2 database), including 2 homozygotes (Sickkids database). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function has shown that chloride transport by the variant is less than 1% (e.g.Sosnay_2013, Van Goor_2013). Three ClinVar submitters including an expert panel (CFTR2) have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)

Pathogenic (Aug 08, 2022) N Not contributing to aggregate classification	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: SCV002570359.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (4) PubMed: 23891399‚ 23974870‚ 30046002‚ 30888834 Comment: Disease-causing CFTR variant. See www.CFTR2.org for phenotypic information.

Pathogenic (Sep 07, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bronchiectasis with or without elevated sweat chloride 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004213397.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023

Likely pathogenic (Sep 05, 2022) N Not contributing to aggregate classification	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: SCV002573986.1 First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022	Comment: 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 … (more) 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, PM3, PM2_SUP, PP3, PP4 (less) Number of individuals with the variant: 1

Pathogenic (Apr 07, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Bronchiectasis with or without elevated sweat chloride 1 Cystic fibrosis Congenital bilateral aplasia of vas deferens from CFTR mutation 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: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV002808765.2 First in ClinVar: Dec 31, 2022 Last updated: Jan 25, 2025

Pathogenic (Aug 28, 2024) N Not contributing to aggregate classification	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: SCV002260596.4 First in ClinVar: Mar 28, 2022 Last updated: Feb 25, 2025	Publications: PubMed (3) PubMed: 23974870‚ 23891399‚ 30046002 Comment: This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 341 of the CFTR protein (p.Ser341Pro). … (more) This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 341 of the CFTR protein (p.Ser341Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 23974870; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53167). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 23891399, 30046002). For these reasons, this variant has been classified as Pathogenic. (less)

Pathogenic (Sep 16, 2020) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Cystic Fibrosis Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001456059.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

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Comment:

The p.S341P pathogenic mutation (also known as c.1021T>C), located in coding exon 8 of the CFTR gene, results from a T to C substitution at nucleotide position 1021. The serine at codon 341 is replaced by proline, an amino acid with similar properties. In a cohort of individuals with cystic fibrosis, this mutation was identified in 377 individuals and is associated with elevated sweat chloride levels, and a higher rate of Pseudomonas infection (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition, analysis in FRT studies demonstrated reduced CFTR protein levels and undetectable chloride conductance (Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

Variant summary: CFTR c.1021T>C (p.Ser341Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251226 control chromosomes (gnomAD). c.1021T>C has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Sosnay_2013, McCague_2019, CFTR2 database), including 2 homozygotes (Sickkids database). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function has shown that chloride transport by the variant is less than 1% (e.g.Sosnay_2013, Van Goor_2013). Three ClinVar submitters including an expert panel (CFTR2) have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

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, PM3, PM2_SUP, PP3, PP4

Comment:

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 341 of the CFTR protein (p.Ser341Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 23974870; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53167). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 23891399, 30046002). For these reasons, this variant has been classified as Pathogenic.

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
Sequencing as a first-line methodology for cystic fibrosis carrier screening.	Beauchamp KA	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 31036917
Correlating Cystic Fibrosis Transmembrane Conductance Regulator Function with Clinical Features to Inform Precision Treatment of Cystic Fibrosis.	McCague AF	American journal of respiratory and critical care medicine	2019	PMID: 30888834
Residual function of cystic fibrosis mutants predicts response to small molecule CFTR modulators.	Han ST	JCI insight	2018	PMID: 30046002
Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function.	Van Goor F	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2014	PMID: 23891399
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.	Sosnay PR	Nature genetics	2013	PMID: 23974870
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR	-	-	-	-
https://cftr2.org	-	-	-	-

Text-mined citations for rs397508144 ...

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 May 17, 2025

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.1021T>C (p.Ser341Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397508144 ...