NM_000492.4(CFTR):c.92G>T (p.Arg31Leu) AND Cystic fibrosis

Germline classification:: Uncertain significance (6 submissions)
Last evaluated:: Mar 3, 2017
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000577473.8

Allele description [Variation Report for NM_000492.4(CFTR):c.92G>T (p.Arg31Leu)]

NM_000492.4(CFTR):c.92G>T (p.Arg31Leu)

Gene:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.92G>T (p.Arg31Leu)

HGVS:

NC_000007.14:g.117504291G>T
NG_016465.4:g.43508G>T
NM_000492.4:c.92G>TMANE SELECT
NP_000483.3:p.Arg31Leu
NP_000483.3:p.Arg31Leu
LRG_663t1:c.92G>T
LRG_663:g.43508G>T
LRG_663p1:p.Arg31Leu
NC_000007.13:g.117144345G>T
NM_000492.3:c.92G>T
P13569:p.Arg31Leu

Protein change:

R31L

Links:

UniProtKB: P13569#VAR_000103; dbSNP: rs149353983

NCBI 1000 Genomes Browser:

rs149353983

Molecular consequence:

NM_000492.4:c.92G>T - 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
SCV000679484	ClinVar Staff, National Center for Biotechnology Information (NCBI)	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000795721	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Nov 13, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001425298	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001981583	CFTR2	reviewed by expert panel (Submitter's publication and website)	Uncertain significance (Mar 3, 2017)	germline	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002686699	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Oct 3, 2022)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 15536480, 16251901, 16339147, 17098482, 18193900, 23420618, 23846440, 28392015, 29805046, 7537150 Citation Link,
SCV003517738	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 29, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12454843, 16339147, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.

Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, Ramalho AS, Amaral MD, Dorfman R, Zielenski J, Masica DL, Karchin R, Millen L, Thomas PJ, Patrinos GP, Corey M, Lewis MH, Rommens JM, Castellani C, Penland CM, Cutting GR.

Nat Genet. 2013 Oct;45(10):1160-7. doi: 10.1038/ng.2745. Epub 2013 Aug 25.

PubMed [citation]

PMID:: 23974870
PMCID:: PMC3874936

See all PubMed Citations (14)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000679484.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

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

From Counsyl, SCV000795721.1

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

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

From Johns Hopkins Genomics, Johns Hopkins University, SCV001425298.1

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

Description

This variant has been previously reported in patients with a phenotypic consistent with cystic fibrosis and is currently classified as a variant of uncertain significance by three submitters in ClinVar. Functional studies have shown that this variant may lead to reduced protein function, however the impact of this variant is not completely understood at this time. Additionally, this CFTR variant (rs149353983) is rare (<0.1%) in large population datasets (gnomAD: 11/282294 total alleles; 0.0039%; no homozygotes). Two bioinformatic tools queried predict that this substitution would be tolerated, and the arginine residue at this position is evolutionarily conserved across most species assessed. The clinical significance of c.92G>T is uncertain at this time.

#	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 CFTR2, SCV001981583.1

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

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

From Ambry Genetics, SCV002686699.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The p.R31L variant (also known as c.92G>T), located in coding exon 2 of the CFTR gene, results from a G to T substitution at nucleotide position 92. The arginine at codon 31 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in an individual with elevated sweat chloride levels and virtually normal pulmonary and pancreatic function; however, no second CFTR alteration was identified (Zielenski J, Hum. Mutat. 1995; 5(1):43-7). In vitro protein studies show that this alteration causes a reduction in the surface expression of the CFTR protein (Jurkuvenaite A, J. Biol. Chem. 2006 Feb; 281(6):3329-34; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). A different alteration located at the same position, p.R31H, has been identified in an individual with chronic bronchitis without a second alteration (Nakano E et al. Dig. Dis. Sci., 2015 May;60:1297-307; El-Seedy A et al. Cell. Mol. Biol. (Noisy-le-grand), 2016 Nov;62:21-28). Another different alteration located at the same position, p.R31C, has been detected as homozygous in an unaffected individual and heterozygous in individuals with cystic fibrosis symptoms, oligospermia, and pancreatitis (Ghanem N et al. Genomics 1994; 21:434-6; Gallati S et al. Reprod. Biomed. Online 2009; 19:685-94; Gomez Lira M et al. Pancreatology 2001; 1:538-42). In addition, the p.R31C alteration was shown to cause a reduction in the surface expression of the CFTR protein and occurred in fewer patients with pancreatitis than in healthy control individuals (Jurkuvenaite A et al. J. Biol. Chem. 2006; 281:3329-34; LaRusch et al. PLoS Genet, 2014; 10(7):e1004376). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant 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, SCV003517738.1

#	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 arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 31 of the CFTR protein (p.Arg31Leu). This variant is present in population databases (rs149353983, gnomAD 0.008%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 12454843). ClinVar contains an entry for this variant (Variation ID: 54087). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects CFTR function (PMID: 16339147). 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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