NM_000492.4(CFTR):c.1655A>C (p.Gln552Pro) AND Cystic fibrosis

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Sep 5, 2022
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:: RCV001804239.3

Allele description [Variation Report for NM_000492.4(CFTR):c.1655A>C (p.Gln552Pro)]

NM_000492.4(CFTR):c.1655A>C (p.Gln552Pro)

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
LOC111674475:CFTR intron 11 enhancer [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.1655A>C (p.Gln552Pro)

HGVS:

NC_000007.14:g.117587809A>C
NG_016465.4:g.127026A>C
NG_056131.3:g.764A>C
NM_000492.4:c.1655A>CMANE SELECT
NP_000483.3:p.Gln552Pro
LRG_663t1:c.1655A>C
LRG_663:g.127026A>C
NC_000007.13:g.117227863A>C
NM_000492.3:c.1655A>C

Protein change:

Q552P

Links:

dbSNP: rs1791967656

NCBI 1000 Genomes Browser:

rs1791967656

Molecular consequence:

NM_000492.4:c.1655A>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
SCV002051809	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 28, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16989640, 33807078, 25741868
SCV002704706	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Sep 5, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19332488, 33807078 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002051809

Johns Hopkins Genomics, Johns Hopkins University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 28, 2021)

germline

clinical testing

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

SCV002704706

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Sep 5, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (4)

Details of each submission

From Johns Hopkins Genomics, Johns Hopkins University, SCV002051809.1

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

Description

CFTR c.1655A>C has been reported in multiple individuals with features of cystic fibrosis. This CFTR variant is absent from a large population dataset and has not been reported in ClinVar. This variant affects a residue in the highly conserved ABC transporter signature motif that may play a role in ATP hydrolysis. Three bioinformatic tools queried predict that this substitution would be damaging and the glutamine residue at this position is evolutionarily conserved across all species assessed. We consider CFTR c.1655A>C 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

From Ambry Genetics, SCV002704706.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Q552P variant (also known as c.1655A>C), located in coding exon 12 of the CFTR gene, results from an A to C substitution at nucleotide position 1655. The glutamine at codon 552 is replaced by proline, an amino acid with similar properties. This variant has been detected in conjunction with a CFTR likely pathogenic variant in a child with classic cystic fibrosis; however, the phase of the two variants was not specified (Mayer Lacrosniere S et al. Genes (Basel), 2021 03;12:). Based on internal structural analysis, this variant is deleterious as it disrupts the LSGGQ motif at ATP-binding site in CFTR (Hwang TC et al. J Physiol, 2009 May;587:2151-61). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 the majority of available evidence to date, this variant is likely to be 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: Aug 18, 2024

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