VCV000053808.14 - ClinVar

NM_000492.4(CFTR):c.376G>A (p.Gly126Ser)

Germline

Classification

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

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

4 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.376G>A (p.Gly126Ser)

Variation ID: 53808 Accession: VCV000053808.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117531001 (GRCh38) [ NCBI UCSC ] 7: 117171055 (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	May 25, 2025	Jan 21, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.376G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Gly126Ser	missense
NC_000007.14:g.117531001G>A
NC_000007.13:g.117171055G>A
NG_016465.4:g.70218G>A
LRG_663:g.70218G>A
LRG_663t1:c.376G>A	LRG_663p1:p.Gly126Ser

... more HGVS ... less HGVS

Protein change

G126S

Other names

Canonical SPDI

NC_000007.14:117531000:G:A

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 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Links

ClinGen: CA327284 dbSNP: rs397508606 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	3753	6142

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 (3)	criteria provided, conflicting classifications	Sep 1, 2021	RCV000577162.11
not specified	Uncertain significance (1)	criteria provided, single submitter	Jan 21, 2025	RCV002281737.3
Congenital bilateral aplasia of vas deferens from CFTR mutation	Pathogenic (1)	criteria provided, single submitter	Jul 22, 2021	RCV001580452.3

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 (May 03, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV001251851.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Uncertain significance (Sep 01, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Cystic fibrosis	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002214949.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023	Publications: PubMed (6) PubMed: 19181743‚ 25042876‚ 8163293‚ 10439967‚ 23974870‚ 27214204 Comment: show This sequence change replaces glycine with serine at codon 126 of the CFTR protein (p.Gly126Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs397508606, ExAC 0.01%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 19181743, 25042876). This variant is also known as c.508G>A. ClinVar contains an entry for this variant (Variation ID: 53808). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect CFTR function (PMID: 25042876). This variant disrupts the p.Gly126 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8163293, 10439967, 23974870, 27214204). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Pathogenic (Jul 22, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Congenital bilateral aplasia of vas deferens from CFTR mutation	Genome-Nilou Lab Accession: SCV001810345.2 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

Uncertain significance (Jan 21, 2025) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002570623.3 First in ClinVar: Sep 17, 2022 Last updated: May 25, 2025	Publications: PubMed (4) PubMed: 19181743‚ 25042876‚ 35913788‚ 38388235 Comment: show Variant summary: CFTR c.376G>A (p.Gly126Ser) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 250896 control chromosomes (gnomAD). c c.376G>A has been reported in the literature in at least one heterozygous individual affected with congenital bilateral absence of vas deferens (CBAVD), repeated respiratory infections and raised sweat chloride levels without a clinical diagnosis of cystic fibrosis (Sharma_2009). This report, however, does not provide unequivocal conclusions about association of the variant with cystic fibrosis. An experimental study measuring channel function by iodide efflux of the mutant protein compared to WT found to have normal protein maturation process and channel activity (Sharma _2015). However, a recent study conducted by Bihler et al reports approximately 25% of normal chloride channel conductance relative to wild type (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 19181743, 25042876, 38388235, 35913788). ClinVar contains an entry for this variant (Variation ID: 53808). Based on the evidence outlined above, the variant was classified as VUS-possibly 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

not provided (-) N Not contributing to aggregate classification	no classification provided	CFTR-related disorders	ClinVar Staff, National Center for Biotechnology Information (NCBI) Accession: SCV000679449.1 First in ClinVar: Jan 25, 2018 Last updated: Jan 25, 2018	Publications: PubMed (1) PubMed: 19181743 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:

This sequence change replaces glycine with serine at codon 126 of the CFTR protein (p.Gly126Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs397508606, ExAC 0.01%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 19181743, 25042876). This variant is also known as c.508G>A. ClinVar contains an entry for this variant (Variation ID: 53808). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect CFTR function (PMID: 25042876). This variant disrupts the p.Gly126 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8163293, 10439967, 23974870, 27214204). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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:

Variant summary: CFTR c.376G>A (p.Gly126Ser) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 250896 control chromosomes (gnomAD). c c.376G>A has been reported in the literature in at least one heterozygous individual affected with congenital bilateral absence of vas deferens (CBAVD), repeated respiratory infections and raised sweat chloride levels without a clinical diagnosis of cystic fibrosis (Sharma_2009). This report, however, does not provide unequivocal conclusions about association of the variant with cystic fibrosis. An experimental study measuring channel function by iodide efflux of the mutant protein compared to WT found to have normal protein maturation process and channel activity (Sharma _2015). However, a recent study conducted by Bihler et al reports approximately 25% of normal chloride channel conductance relative to wild type (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 19181743, 25042876, 38388235, 35913788). ClinVar contains an entry for this variant (Variation ID: 53808). Based on the evidence outlined above, the variant was classified as VUS-possibly 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
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
Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California.	Salinas DB	PloS one	2016	PMID: 27214204
Function, pharmacological correction and maturation of new Indian CFTR gene mutations.	Sharma H	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2015	PMID: 25042876
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.	Sosnay PR	Nature genetics	2013	PMID: 23974870
Heterogenous spectrum of CFTR gene mutations in Indian patients with congenital absence of vas deferens.	Sharma N	Human reproduction (Oxford, England)	2009	PMID: 19181743
Two buffer PAGE system-based SSCP/HD analysis: a general protocol for rapid and sensitive mutation screening in cystic fibrosis and any other human genetic disease.	Liechti-Gallati S	European journal of human genetics : EJHG	1999	PMID: 10439967
A new missense mutation G126D in exon 4 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.	Wagner K	Human heredity	1994	PMID: 8163293

Text-mined citations for rs397508606 ...

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 25, 2025

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.376G>A (p.Gly126Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Text-mined citations for rs397508606 ...