VCV002498346.2 - ClinVar

NM_000492.4(CFTR):c.2851A>G (p.Lys951Glu)

Germline

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.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000492.4(CFTR):c.2851A>G (p.Lys951Glu)

Variation ID: 2498346 Accession: VCV002498346.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117603725 (GRCh38) [ NCBI UCSC ] 7: 117243779 (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	Apr 23, 2023	May 1, 2024	Oct 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.2851A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Lys951Glu	missense
NC_000007.14:g.117603725A>G
NC_000007.13:g.117243779A>G
NG_016465.4:g.142942A>G
LRG_663:g.142942A>G
LRG_663t1:c.2851A>G	LRG_663p1:p.Lys951Glu

... more HGVS ... less HGVS

Protein change

K951E

Other names

Canonical SPDI

NC_000007.14:117603724:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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

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		-	-	GRCh38 GRCh37	3832	5210

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	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 26, 2023	RCV003222555.2

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.	More information 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 (Apr 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: germline	Department of Human Genetics, Hannover Medical School Accession: SCV003915964.1 First in ClinVar: Apr 23, 2023 Last updated: Apr 23, 2023	Comment: In the CFTR-France database, this missense variant is also evaluated as a VUS, but it is not listed in other variant databases. In the population … (more) In the CFTR-France database, this missense variant is also evaluated as a VUS, but it is not listed in other variant databases. In the population database gnomAD, the variant is listed in the African population (allele frequencies: AFR 0.028%, ALL 0.0025%). An in silico analysis of this change using the programme REVEL did not show a clear result. In the literature, the variant was reported in a patient with COPD (PMID 34996830) and in a fetus with hyperechogenic intestine and another CFTR variant (p.(Gly622Asp), variant with different clinical consequences according to the CFTR2 database) (PMID 25443471). A conclusive evaluation of the variant is currently not possible on the basis of the available data. (less) Clinical Features: Recurrent sinusitis (present)
Uncertain significance (Oct 26, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005035945.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 25443471‚ 28603918 Comment: The p.K951E variant (also known as c.2851A>G), located in coding exon 17 of the CFTR gene, results from an A to G substitution at nucleotide … (more) The p.K951E variant (also known as c.2851A>G), located in coding exon 17 of the CFTR gene, results from an A to G substitution at nucleotide position 2851. The lysine at codon 951 is replaced by glutamic acid, an amino acid with similar properties. This alteration is included in CFTR-France, a database that includes CFTR genotypes from 4615 individuals affected with CF, CF related disease, suspected CF, or CF carriers; this variant is classified as a VUS in this database (Claustres M et al. Hum Mutat, 2017 Oct;38:1297-1315). This alteration was also observed in a fetus with hyperechoic bowel who appeared to be asymptomatic at birth after neonatal screening (Marion H et al. J Cyst Fibros, 2015 May;14:305-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

In the CFTR-France database, this missense variant is also evaluated as a VUS, but it is not listed in other variant databases. In the population database gnomAD, the variant is listed in the African population (allele frequencies: AFR 0.028%, ALL 0.0025%). An in silico analysis of this change using the programme REVEL did not show a clear result. In the literature, the variant was reported in a patient with COPD (PMID 34996830) and in a fetus with hyperechogenic intestine and another CFTR variant (p.(Gly622Asp), variant with different clinical consequences according to the CFTR2 database) (PMID 25443471). A conclusive evaluation of the variant is currently not possible on the basis of the available data.

Comment:

The p.K951E variant (also known as c.2851A>G), located in coding exon 17 of the CFTR gene, results from an A to G substitution at nucleotide position 2851. The lysine at codon 951 is replaced by glutamic acid, an amino acid with similar properties. This alteration is included in CFTR-France, a database that includes CFTR genotypes from 4615 individuals affected with CF, CF related disease, suspected CF, or CF carriers; this variant is classified as a VUS in this database (Claustres M et al. Hum Mutat, 2017 Oct;38:1297-1315). This alteration was also observed in a fetus with hyperechoic bowel who appeared to be asymptomatic at birth after neonatal screening (Marion H et al. J Cyst Fibros, 2015 May;14:305-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants.	Claustres M	Human mutation	2017	PMID: 28603918
The p.Gly622Asp (G622D) mutation, frequently found in Reunion Island and in black populations, is associated with a wide spectrum of CF and CFTR-RD phenotypes.	Marion H	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2015	PMID: 25443471

Text-mined citations for this variant ...

Record last updated May 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.2851A>G (p.Lys951Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...