NM_000492.4(CFTR):c.1390A>C (p.Lys464Gln) AND Cystic fibrosis

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 18, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002396669.4

Allele description [Variation Report for NM_000492.4(CFTR):c.1390A>C (p.Lys464Gln)]

NM_000492.4(CFTR):c.1390A>C (p.Lys464Gln)

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>C (p.Lys464Gln)

HGVS:

NC_000007.14:g.117548821A>C
NG_016465.4:g.88038A>C
NM_000492.4:c.1390A>CMANE SELECT
NP_000483.3:p.Lys464Gln
NP_000483.3:p.Lys464Gln
LRG_663t1:c.1390A>C
LRG_663:g.88038A>C
LRG_663p1:p.Lys464Gln
NC_000007.13:g.117188875A>C
NM_000492.3:c.1390A>C

Protein change:

K464Q

Molecular consequence:

NM_000492.4:c.1390A>C - 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
SCV002698387	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Aug 7, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004300563	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 18, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30420730, 32777524, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002698387

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Aug 7, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV004300563

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 18, 2023)

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

Functional roles of the nucleotide-binding folds in the activation of the cystic fibrosis transmembrane conductance regulator.

Smit LS, Wilkinson DJ, Mansoura MK, Collins FS, Dawson DC.

Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):9963-7.

PubMed [citation]

PMID:: 7694298
PMCID:: PMC47693

SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis.

Zou WB, Tang XY, Zhou DZ, Qian YY, Hu LH, Yu FF, Yu D, Wu H, Deng SJ, Lin JH, Zhao AJ, Zhao ZH, Wu HY, Zhu JH, Qian W, Wang L, Xin L, Wang MJ, Wang LJ, Fang X, He L, Masson E, et al.

Clin Transl Gastroenterol. 2018 Nov 12;9(11):204. doi: 10.1038/s41424-018-0069-5.

PubMed [citation]

PMID:: 30420730
PMCID:: PMC6232107

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV002698387.2

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

Description

The p.K464Q variant (also known as c.1390A>C), located in coding exon 10 of the CFTR gene, results from an A to C substitution at nucleotide position 1390. The lysine at codon 464 is replaced by glutamine, an amino acid with similar properties. In Xenopus oocytes, this variant demonstrated reduced sensitivity of CFTR to activation similar to p.G551S (Smit LS et al. Proc. Natl. Acad. Sci. U.S.A., 1993 Nov;90:9963-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004300563.1

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

Description

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 464 of the CFTR protein (p.Lys464Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CFTR-related conditions and/or congenital absence of vas deferens (PMID: 30420730, 32777524; Invitae). ClinVar contains an entry for this variant (Variation ID: 1771535). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.

#	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: Sep 29, 2024

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