NM_000492.4(CFTR):c.1546A>G (p.Arg516Gly) AND Cystic fibrosis

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 24, 2023
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:: RCV002405289.3

Allele description [Variation Report for NM_000492.4(CFTR):c.1546A>G (p.Arg516Gly)]

NM_000492.4(CFTR):c.1546A>G (p.Arg516Gly)

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.1546A>G (p.Arg516Gly)

HGVS:

NC_000007.14:g.117559617A>G
NG_016465.4:g.98834A>G
NM_000492.4:c.1546A>GMANE SELECT
NP_000483.3:p.Arg516Gly
NP_000483.3:p.Arg516Gly
LRG_663t1:c.1546A>G
LRG_663:g.98834A>G
LRG_663p1:p.Arg516Gly
NC_000007.13:g.117199671A>G
NM_000492.3:c.1546A>G

Protein change:

R516G

Links:

dbSNP: rs397508226

NCBI 1000 Genomes Browser:

rs397508226

Molecular consequence:

NM_000492.4:c.1546A>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
SCV002706291	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Apr 24, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31344706, 34782259 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002706291

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Apr 24, 2023)

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

Image-based β-adrenergic sweat rate assay captures minimal cystic fibrosis transmembrane conductance regulator function.

Salinas DB, Peng YH, Horwich B, Wee CP, Frisbee E, Maarek JM.

Pediatr Res. 2020 Jan;87(1):137-145. doi: 10.1038/s41390-019-0503-8. Epub 2019 Jul 25.

PubMed [citation]

PMID:: 31344706
PMCID:: PMC6962560

Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment.

Raraigh KS, Aksit MA, Hetrick K, Pace RG, Ling H, O'Neal W, Blue E, Zhou YH, Bamshad MJ, Blackman SM, Gibson RL, Knowles MR, Cutting GR.

J Cyst Fibros. 2022 May;21(3):463-470. doi: 10.1016/j.jcf.2021.10.011. Epub 2021 Nov 12.

PubMed [citation]

PMID:: 34782259

Details of each submission

From Ambry Genetics, SCV002706291.3

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

Description

The p.R516G variant (also known as c.1546A>G), located in coding exon 11 of the CFTR gene, results from an A to G substitution at nucleotide position 1546. The arginine at codon 516 is replaced by glycine, an amino acid with dissimilar properties. This variant has been detected in conjunction with a CFTR pathogenic variant in two individuals with cystic fibrosis (Salinas DB et al. Pediatr Res, 2020 Jan;87:137-145; Raraigh KS et al. J Cyst Fibros, 2022 May;21:463-470). This variant has <10% of normal CFTR function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 04/21/2023). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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: May 1, 2024

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