NM_000492.4(CFTR):c.1390A>G (p.Lys464Glu) AND Cystic fibrosis

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 19, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001250572.1

Allele description [Variation Report for NM_000492.4(CFTR):c.1390A>G (p.Lys464Glu)]

NM_000492.4(CFTR):c.1390A>G (p.Lys464Glu)

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
CFTR-AS1:CFTR antisense RNA 1 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.1390A>G (p.Lys464Glu)

HGVS:

NC_000007.14:g.117548821A>G
NG_016465.4:g.88038A>G
NM_000492.4:c.1390A>GMANE SELECT
NP_000483.3:p.Lys464Glu
LRG_663t1:c.1390A>G
LRG_663:g.88038A>G
NC_000007.13:g.117188875A>G
NM_000492.3:c.1390A>G

Protein change:

K464E

Links:

dbSNP: rs1799216615

NCBI 1000 Genomes Browser:

rs1799216615

Molecular consequence:

NM_000492.4:c.1390A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001425432	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 19, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11882668, 16989640, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001425432

Johns Hopkins Genomics, Johns Hopkins University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 19, 2020)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation of Walker-A lysine 464 in cystic fibrosis transmembrane conductance regulator reveals functional interaction between its nucleotide-binding domains.

Powe AC Jr, Al-Nakkash L, Li M, Hwang TC.

J Physiol. 2002 Mar 1;539(Pt 2):333-46.

PubMed [citation]

PMID:: 11882668
PMCID:: PMC2290141

The Walker B motif of the second nucleotide-binding domain (NBD2) of CFTR plays a key role in ATPase activity by the NBD1-NBD2 heterodimer.

Stratford FL, Ramjeesingh M, Cheung JC, Huan LJ, Bear CE.

Biochem J. 2007 Jan 15;401(2):581-6.

PubMed [citation]

PMID:: 16989640
PMCID:: PMC1820796

See all PubMed Citations (3)

Details of each submission

From Johns Hopkins Genomics, Johns Hopkins University, SCV001425432.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant has been identified in patients with features of cystic fibrosis and it is absent from a large population dataset. The lysine residue at this position is predicted to be in the highly conserved Walker A motif of the first nucleotide binding domain of CFTR. The functional consequence of p.Lys464Glu has not been assessed, but studies of a different substitution at this residue (p.Lys464Ala) demonstrate the importance of this amino acid in CFTR function. Three bioinformatics tools predict that p.Lys464Glu would possibly be damaging and lysine at this position is evolutionarily conserved among all species assessed. We consider c.1390A>G to be likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 23, 2022

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