VCV000053692.11 - ClinVar

NM_000492.4(CFTR):c.323C>T (p.Ser108Phe)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(2); Uncertain significance(2)

5 out of 7 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000492.4(CFTR):c.323C>T (p.Ser108Phe)

Variation ID: 53692 Accession: VCV000053692.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117530948 (GRCh38) [ NCBI UCSC ] 7: 117171002 (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 25, 2018	Jun 29, 2025	Jan 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.323C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Ser108Phe	missense
NC_000007.14:g.117530948C>T
NC_000007.13:g.117171002C>T
NG_016465.4:g.70165C>T
LRG_663:g.70165C>T
LRG_663t1:c.323C>T	LRG_663p1:p.Ser108Phe

... more HGVS ... less HGVS

Protein change

S108F

Other names

Canonical SPDI

NC_000007.14:117530947:C:T

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.

Links

ClinGen: CA327108 dbSNP: rs397508520 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	3800	6217

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 classifications of pathogenicity (5)	criteria provided, conflicting classifications	Sep 5, 2022	RCV000577153.11
CFTR-related disorder Cystic fibrosis	Pathogenic (1)	criteria provided, single submitter	Jan 29, 2018	RCV001009379.1
Bronchiectasis with or without elevated sweat chloride 1	Likely pathogenic (1)	criteria provided, single submitter	Jan 23, 2023	RCV003466910.1

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.	Expand all rows Collapse all rows 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 pathogenic (Jan 23, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Bronchiectasis with or without elevated sweat chloride 1	Baylor Genetics Accession: SCV004215205.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain significance (Mar 23, 2017) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cystic fibrosis	Ambry Genetics Accession: SCV002611769.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 11278813‚ 15480987‚ 9150843 Comment: show The p.S108F variant (also known as c.323C>T), located in coding exon 4 of the CFTR gene, results from a C to T substitution at nucleotide position 323. The serine at codon 108 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was identified in an individual with elevated sweat chloride levels and cystic fibrosis in conjunction with p.F508del and (TG)12-5T poly T variant; however, the phase of these alterations was not confirmed (Hirtz S et al. Gastroenterology, 2004 Oct;127:1085-95). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Jul 22, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Genome-Nilou Lab Accession: SCV001821989.2 First in ClinVar: Sep 08, 2021 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no Sex: mixed

Pathogenic (Jan 29, 2018) C Contributing to aggregate classification	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017))	cystic fibrosis CFTR-related disorders	CFTR-France Accession: SCV001169232.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Publications: PubMed (1) PubMed: 28603918 Comment: show when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: yes Observation 1 Collection method: curation Allele origin: germline Affected status: yes

Uncertain significance (Sep 05, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002574026.1 First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022	Comment: show 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: PM3, PM2_SUP, PP3, PP4 (less) Observation: 1 Collection method: curation Allele origin: unknown Affected status: yes more Observation 1 Collection method: curation Allele origin: unknown Affected status: yes Number of individuals with the variant: 2

Uncertain significance (May 22, 2018) N Not contributing to aggregate classification	no assertion criteria provided	Cystic fibrosis	Counsyl Accession: SCV000800102.2 First in ClinVar: Jan 25, 2018 Last updated: Jun 29, 2025	Publications: PubMed (2) PubMed: 11278813‚ 15480987 Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

not provided (-) N Not contributing to aggregate classification	no classification provided	CFTR-related disorders	ClinVar Staff, National Center for Biotechnology Information (NCBI) Accession: SCV000679039.1 First in ClinVar: Jan 25, 2018 Last updated: Jan 25, 2018	Publications: PubMed (2) PubMed: 15480987‚ 9150843 Observation: 1 Collection method: literature only Allele origin: germline Affected status: yes Observation 1 Collection method: literature only Allele origin: germline Affected status: yes

Comment:

The p.S108F variant (also known as c.323C>T), located in coding exon 4 of the CFTR gene, results from a C to T substitution at nucleotide position 323. The serine at codon 108 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was identified in an individual with elevated sweat chloride levels and cystic fibrosis in conjunction with p.F508del and (TG)12-5T poly T variant; however, the phase of these alterations was not confirmed (Hirtz S et al. Gastroenterology, 2004 Oct;127:1085-95). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.

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: PM3, PM2_SUP, PP3, PP4

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis.	Hirtz S	Gastroenterology	2004	PMID: 15480987
Disease-associated mutations in the extracytoplasmic loops of cystic fibrosis transmembrane conductance regulator do not impede biosynthetic processing but impair chloride channel stability.	Hämmerle MM	The Journal of biological chemistry	2001	PMID: 11278813
Molecular diagnosis of congenital bilateral absence of the vas deferens: analyses of the CFTR gene in 64 French patients.	Bienvenu T	Annales de genetique	1997	PMID: 9150843

Text-mined citations for rs397508520 ...

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 Jun 29, 2025