VCV000053611.7 - ClinVar

NM_000492.4(CFTR):c.2977G>T (p.Asp993Tyr)

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 6 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.2977G>T (p.Asp993Tyr)

Variation ID: 53611 Accession: VCV000053611.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117606742 (GRCh38) [ NCBI UCSC ] 7: 117246796 (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	Jan 25, 2025	Jan 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.2977G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Asp993Tyr	missense
NC_000007.14:g.117606742G>T
NC_000007.13:g.117246796G>T
NG_016465.4:g.145959G>T
LRG_663:g.145959G>T
LRG_663t1:c.2977G>T	LRG_663p1:p.Asp993Tyr

... more HGVS ... less HGVS

Protein change

D993Y

Other names

Canonical SPDI

NC_000007.14:117606741: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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA326993 dbSNP: rs397508468 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-AS2	-	-	-	GRCh38	-	1248

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	Jan 29, 2018	RCV000577451.6
Bronchiectasis with or without elevated sweat chloride 1	Likely pathogenic (1)	criteria provided, single submitter	Sep 3, 2023	RCV003474561.1
not specified	Uncertain significance (1)	criteria provided, single submitter	Feb 1, 2023	RCV003155058.1
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	Jan 23, 2024	RCV005042141.1

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 (Sep 03, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Bronchiectasis with or without elevated sweat chloride 1	Baylor Genetics Accession: SCV004213408.1 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 (Jun 24, 2014) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cystic fibrosis	Ambry Genetics Accession: SCV002751366.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 15698946‚ 22483971 Comment: show The p.D993Y variant (also known as c.2977G>T), located in coding exon 18 of the CFTR gene, results from a G to T substitution at nucleotide position 2977. The aspartic acid at codon 993 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was reportedly detected in trans with deltaF508 in the CFTR gene in two patients with severe lung disease, a positive sweat test, who were pancreatic insufficient (Claustres et al. Cystic Fibrosis Mutation Database [database online] Toronto, ON, Canada: SickKids; 1995 & 1997). This variant was also reported in a Chinese male with CBAVD; a second alteration was not identified (Li H et al. J Cyst Fibros. 2012;11(4):316-23). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6493 samples (12986 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant 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

Pathogenic (Jan 29, 2018) C Contributing to aggregate classification	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017))	cystic fibrosis	CFTR-France Accession: SCV001169495.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Publications: PubMed (1) PubMed: 28603918 Observation: 1 Collection method: curation Allele origin: germline Affected status: yes Observation 1 Collection method: curation Allele origin: germline Affected status: yes

Uncertain significance (Feb 01, 2023) 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: SCV003844824.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Publications: PubMed (3) PubMed: 10923036‚ 15698946‚ 15463906 Comment: show Variant summary: CFTR c.2977G>T (p.Asp993Tyr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of 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 251120 control chromosomes (gnomAD). c.2977G>T has been reported in the literature in individuals affected with Cystic Fibrosis (e.g. Claustres_2000, des Georges_2004, Dugueperoux_2004). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as pathogenic. 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

Likely pathogenic (Jan 23, 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: SCV005666396.1 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

not provided (-) N Not contributing to aggregate classification	no classification provided	CFTR-related disorders	ClinVar Staff, National Center for Biotechnology Information (NCBI) Accession: SCV000679365.1 First in ClinVar: Jan 25, 2018 Last updated: Jan 25, 2018	Publications: PubMed (1) PubMed: 15698946 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.D993Y variant (also known as c.2977G>T), located in coding exon 18 of the CFTR gene, results from a G to T substitution at nucleotide position 2977. The aspartic acid at codon 993 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was reportedly detected in trans with deltaF508 in the CFTR gene in two patients with severe lung disease, a positive sweat test, who were pancreatic insufficient (Claustres et al. Cystic Fibrosis Mutation Database [database online] Toronto, ON, Canada: SickKids; 1995 & 1997). This variant was also reported in a Chinese male with CBAVD; a second alteration was not identified (Li H et al. J Cyst Fibros. 2012;11(4):316-23). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6493 samples (12986 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.

Comment:

Variant summary: CFTR c.2977G>T (p.Asp993Tyr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of 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 251120 control chromosomes (gnomAD). c.2977G>T has been reported in the literature in individuals affected with Cystic Fibrosis (e.g. Claustres_2000, des Georges_2004, Dugueperoux_2004). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as pathogenic. 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
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens.	Li H	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2012	PMID: 22483971
High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France.	des Georges M	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2004	PMID: 15698946
Cystic fibrosis at the Reunion Island (France): spectrum of mutations and genotype-phenotype for the Y122X mutation.	Duguépéroux I	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2004	PMID: 15463906
Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France.	Claustres M	Human mutation	2000	PMID: 10923036

Text-mined citations for rs397508468 ...

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 Aug 09, 2025