VCV000553569.5 - ClinVar

NM_000492.4(CFTR):c.1352G>T (p.Gly451Val)

Germline

Classification

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

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

3 out of 4 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.1352G>T (p.Gly451Val)

Variation ID: 553569 Accession: VCV000553569.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117548783 (GRCh38) [ NCBI UCSC ] 7: 117188837 (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	Aug 5, 2018	Dec 14, 2025	Sep 15, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.1352G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Gly451Val	missense
NC_000007.14:g.117548783G>T
NC_000007.13:g.117188837G>T
NG_016465.4:g.88000G>T
LRG_663:g.88000G>T
LRG_663t1:c.1352G>T	LRG_663p1:p.Gly451Val

... more HGVS ... less HGVS

Protein change

G451V

Other names

Canonical SPDI

NC_000007.14:117548782:G: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) 0.00000

Links

ClinGen: CA368982277 dbSNP: rs1554382653 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
CFTR-AS1	-	-	-	GRCh38	-	612

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	Likely pathogenic (2)	criteria provided, single submitter	Sep 15, 2025	RCV000669047.3
not provided	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2023	RCV004702286.1
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	Jun 12, 2024	RCV005034250.1

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.
Uncertain significance (Oct 31, 2023) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Not Provided	GeneDx Accession: SCV005201947.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Comment: show Reported on the same chromosome (in cis) as p.(Gly253Arg) in heterozygous or homozygous state in multiple individuals with cystic fibrosis from Ecuador, but additional clinical information and familial segregation information was not included (PMID: 30763667); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32596391, 32429104, 16189704, 35698092, 30763667) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Jun 12, 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: SCV005673318.1 First in ClinVar: Jan 25, 2025 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

Likely pathogenic (Sep 15, 2025) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Cystic fibrosis	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005204831.2 First in ClinVar: Sep 16, 2024 Last updated: Dec 14, 2025	Publications: PubMed (8) PubMed: 16189704‚ 32429104‚ 30763667‚ 35698092‚ 35858753‚ 38388235‚ 34613844‚ 37701179 Comment: show Variant summary: CFTR c.1352G>T (p.Gly451Val) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 244264 control chromosomes. c.1352G>T has been observed in heterozygous, presumed compound heterozygous, and complex presumed compound heterozygous (sharing an allele with another rare VUS p.Gly253Arg) states in multiple individuals affected with Cystic Fibrosis and/or CFTR-related conditions (example: McGinness_2005, Petrova_2020, Rueda-Nieto_2022, Ruiz-Cabezas_2019, Shen_2022, Woodall_2021, Woodall_2023). The impact of the complex allele consisting of c.[757G>A;1352G>T] p.[(Gly253Arg;Gly451Val)] may be pathogenic as it has been seen in several individuals affected with cystic fibrosis-spectrum disease with various presumed compound heterozygous pathogenic variants on the second allele (example: Ruiz-Cabezas_2019); however, the impact of p.Gly451Val alone cannot be disambiguated. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 16.37% of normal chloride channel conductance relative to wild type (example: Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 16189704, 32429104, 30763667, 35698092, 35858753, 34613844, 37701179, 38388235). ClinVar contains an entry for this variant (Variation ID: 553569). 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

Uncertain significance (Aug 30, 2017) N Not contributing to aggregate classification	no assertion criteria provided	Cystic fibrosis	Counsyl Accession: SCV000793746.2 First in ClinVar: Aug 05, 2018 Last updated: Jun 29, 2025	Publications: PubMed (1) PubMed: 16189704 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

Comment:

Reported on the same chromosome (in cis) as p.(Gly253Arg) in heterozygous or homozygous state in multiple individuals with cystic fibrosis from Ecuador, but additional clinical information and familial segregation information was not included (PMID: 30763667); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32596391, 32429104, 16189704, 35698092, 30763667)

Comment:

Variant summary: CFTR c.1352G>T (p.Gly451Val) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 244264 control chromosomes. c.1352G>T has been observed in heterozygous, presumed compound heterozygous, and complex presumed compound heterozygous (sharing an allele with another rare VUS p.Gly253Arg) states in multiple individuals affected with Cystic Fibrosis and/or CFTR-related conditions (example: McGinness_2005, Petrova_2020, Rueda-Nieto_2022, Ruiz-Cabezas_2019, Shen_2022, Woodall_2021, Woodall_2023). The impact of the complex allele consisting of c.[757G>A;1352G>T] p.[(Gly253Arg;Gly451Val)] may be pathogenic as it has been seen in several individuals affected with cystic fibrosis-spectrum disease with various presumed compound heterozygous pathogenic variants on the second allele (example: Ruiz-Cabezas_2019); however, the impact of p.Gly451Val alone cannot be disambiguated. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 16.37% of normal chloride channel conductance relative to wild type (example: Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 16189704, 32429104, 30763667, 35698092, 35858753, 34613844, 37701179, 38388235). ClinVar contains an entry for this variant (Variation ID: 553569). 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
In vitro modulator responsiveness of 655 CFTR variants found in people with cystic fibrosis.	Bihler H	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2024	PMID: 38388235
Expression of gain-of-function CFTR in cystic fibrosis airway cells restores epithelial function better than wild-type or codon-optimized CFTR.	Woodall M	Molecular therapy. Methods & clinical development	2023	PMID: 37701179
Genetic spectrum of Chinese children with cystic fibrosis: comprehensive data analysis from the main referral centre in China.	Shen Y	Journal of medical genetics	2022	PMID: 35858753
Analysis of the genotypic profile and its relationship with the clinical manifestations in people with cystic fibrosis: study from a rare disease registry.	Rueda-Nieto S	Orphanet journal of rare diseases	2022	PMID: 35698092
Culture with apically applied healthy or disease sputum alters the airway surface liquid proteome and ion transport across human bronchial epithelial cells.	Woodall M	American journal of physiology. Cell physiology	2021	PMID: 34613844
Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients.	Petrova NV	Genes	2020	PMID: 32429104
Mutational analysis of CFTR in the Ecuadorian population using next-generation sequencing.	Ruiz-Cabezas JC	Gene	2019	PMID: 30763667
Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples.	McGinniss MJ	Human genetics	2005	PMID: 16189704

Text-mined citations for rs1554382653 ...

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 Dec 14, 2025