VCV000053245.12 - ClinVar

NM_000492.4(CFTR):c.1397C>T (p.Ser466Leu)

Germline

Classification

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

Conflicting classifications of pathogenicity
Likely pathogenic(4); Uncertain significance(1)

5 out of 5 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.1397C>T (p.Ser466Leu)

Variation ID: 53245 Accession: VCV000053245.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117559468 (GRCh38) [ NCBI UCSC ] 7: 117199522 (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	Jun 22, 2020	Jul 13, 2025	May 28, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.1397C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Ser466Leu	missense
NC_000007.14:g.117559468C>T
NC_000007.13:g.117199522C>T
NG_016465.4:g.98685C>T
LRG_663:g.98685C>T
LRG_663t1:c.1397C>T	LRG_663p1:p.Ser466Leu

... more HGVS ... less HGVS

Protein change

S466L

Other names

Canonical SPDI

NC_000007.14:117559467: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA326469 dbSNP: rs121908805 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	3863	6322
CFTR-AS1	-	-	-	GRCh38	-	624

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.
Congenital bilateral aplasia of vas deferens from CFTR mutation	Likely pathogenic (1)	criteria provided, single submitter	Aug 9, 2024	RCV001192400.3
Bronchiectasis with or without elevated sweat chloride 1 Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Hereditary pancreatitis	Likely pathogenic (1)	criteria provided, single submitter	Mar 30, 2024	RCV002496708.2
Bronchiectasis with or without elevated sweat chloride 1	Likely pathogenic (1)	criteria provided, single submitter	Sep 21, 2023	RCV003473453.1
Cystic fibrosis	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	May 28, 2025	RCV002390195.8

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.
Uncertain significance (Aug 05, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Cystic fibrosis	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003271454.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (4) PubMed: 20021716‚ 21520337‚ 26277102‚ 11597353 Comment: show This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 466 of the CFTR protein (p.Ser466Leu). This variant is present in population databases (rs121908805, gnomAD 0.0009%). This missense change has been observed in individuals with congenital absence of the vas deferens (PMID: 20021716, 21520337, 26277102). ClinVar contains an entry for this variant (Variation ID: 53245). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CFTR function (PMID: 11597353). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (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 (Sep 21, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Bronchiectasis with or without elevated sweat chloride 1	Baylor Genetics Accession: SCV004213365.1 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

Likely pathogenic (May 28, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cystic fibrosis	Ambry Genetics Accession: SCV002697683.4 First in ClinVar: Nov 29, 2022 Last updated: Jul 13, 2025	Publications: PubMed (3) PubMed: 11597353‚ 20021716‚ 21520337 Comment: show The p.S466L variant (also known as c.1397C>T), located in coding exon 11 of the CFTR gene, results from a C to T substitution at nucleotide position 1397. The serine at codon 466 is replaced by leucine, an amino acid with dissimilar properties. This variant was identified in one individual diagnosed with azoospermia; however, complete genotype information was not provided (Gallati S et al. Reprod. Biomed. Online, 2009 Nov;19:685-94). It was also detected in conjunction with a nonsense alteration in an individual with congenital absence of the vas deferens (CBAVD) (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). In addition, this variant demonstrated reduced chloride function when expressed in Xenopus oocytes (Boucherot A et al. Biochim. Biophys. Acta, 2001 Nov;1515:64-71). 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 the majority of available evidence to date, this variant is likely to be pathogenic. (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 (Aug 09, 2024) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Congenital bilateral aplasia of vas deferens from CFTR mutation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001360487.3 First in ClinVar: Jun 22, 2020 Last updated: Oct 26, 2024	Publications: PubMed (9) PubMed: 20021716‚ 21520337‚ 11504857‚ 25735457‚ 25880441‚ 29497617‚ 11597353‚ 26277102‚ 35913788 Comment: show Variant summary: CFTR c.1397C>T (p.Ser466Leu) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) 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 251204 control chromosomes. c.1397C>T has been reported in at least two compound heterozygous individuals affected with Congenital Bilateral Absence of the Vas Deferens (CBAVD), where both of these patients also carried a well-known CFTR disease variant (Steiner_2011 and in the SickKids database). At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating that the variant protein in Xenopus oocytes has a significantly decreased Cl- channel function, with a residual whole cell Cl- conductance of about 8-10% of the wild type (Boucherot_2001). The following publications have been ascertained in the context of this evaluation (PMID: 11597353, 11504857, 35913788, 20021716, 25880441, 29497617, 25735457, 21520337, 26277102). ClinVar contains an entry for this variant (Variation ID: 53245). Based on the evidence outlined above, the variant was classified as likely pathogenic. (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 (Mar 30, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	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.	Fulgent Genetics, Fulgent Genetics Accession: SCV002807599.2 First in ClinVar: Dec 31, 2022 Last updated: Jan 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 466 of the CFTR protein (p.Ser466Leu). This variant is present in population databases (rs121908805, gnomAD 0.0009%). This missense change has been observed in individuals with congenital absence of the vas deferens (PMID: 20021716, 21520337, 26277102). ClinVar contains an entry for this variant (Variation ID: 53245). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CFTR function (PMID: 11597353). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The p.S466L variant (also known as c.1397C>T), located in coding exon 11 of the CFTR gene, results from a C to T substitution at nucleotide position 1397. The serine at codon 466 is replaced by leucine, an amino acid with dissimilar properties. This variant was identified in one individual diagnosed with azoospermia; however, complete genotype information was not provided (Gallati S et al. Reprod. Biomed. Online, 2009 Nov;19:685-94). It was also detected in conjunction with a nonsense alteration in an individual with congenital absence of the vas deferens (CBAVD) (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). In addition, this variant demonstrated reduced chloride function when expressed in Xenopus oocytes (Boucherot A et al. Biochim. Biophys. Acta, 2001 Nov;1515:64-71). 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 the majority of available evidence to date, this variant is likely to be pathogenic.

Comment:

Variant summary: CFTR c.1397C>T (p.Ser466Leu) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) 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 251204 control chromosomes. c.1397C>T has been reported in at least two compound heterozygous individuals affected with Congenital Bilateral Absence of the Vas Deferens (CBAVD), where both of these patients also carried a well-known CFTR disease variant (Steiner_2011 and in the SickKids database). At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating that the variant protein in Xenopus oocytes has a significantly decreased Cl- channel function, with a residual whole cell Cl- conductance of about 8-10% of the wild type (Boucherot_2001). The following publications have been ascertained in the context of this evaluation (PMID: 11597353, 11504857, 35913788, 20021716, 25880441, 29497617, 25735457, 21520337, 26277102). ClinVar contains an entry for this variant (Variation ID: 53245). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Heterogeneous spectrum of CFTR gene mutations in Chinese patients with CAVD and the dilemma of genetic blocking strategy.	Feng J	Reproduction (Cambridge, England)	2022	PMID: 35913788
Factors influencing readthrough therapy for frequent cystic fibrosis premature termination codons.	Pranke I	ERJ open research	2018	PMID: 29497617
Targeted mutation screening panels expose systematic population bias in detection of cystic fibrosis risk.	Lim RM	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 25880441
Comparative ex vivo, in vitro and in silico analyses of a CFTR splicing mutation: Importance of functional studies to establish disease liability of mutations.	Ramalho AS	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2016	PMID: 25735457
Novel mutations and polymorphisms in the CFTR gene associated with three subtypes of congenital absence of vas deferens.	Yang X	Fertility and sterility	2015	PMID: 26277102
Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens.	Steiner B	Human mutation	2011	PMID: 21520337
Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners.	Gallati S	Reproductive biomedicine online	2009	PMID: 20021716
Role of CFTR's PDZ1-binding domain, NBF1 and Cl(-) conductance in inhibition of epithelial Na(+) channels in Xenopus oocytes.	Boucherot A	Biochimica et biophysica acta	2001	PMID: 11597353
A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models.	Chen JM	Molecular biology and evolution	2001	PMID: 11504857

Text-mined citations for rs121908805 ...

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 Jul 19, 2025