NM_000492.4(CFTR):c.2813T>G (p.Val938Gly) AND Cystic fibrosis

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 10, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001378467.16

Allele description [Variation Report for NM_000492.4(CFTR):c.2813T>G (p.Val938Gly)]

NM_000492.4(CFTR):c.2813T>G (p.Val938Gly)

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.2813T>G (p.Val938Gly)

HGVS:

NC_000007.14:g.117603687T>G
NG_016465.4:g.142904T>G
NM_000492.4:c.2813T>GMANE SELECT
NP_000483.3:p.Val938Gly
NP_000483.3:p.Val938Gly
LRG_663t1:c.2813T>G
LRG_663:g.142904T>G
LRG_663p1:p.Val938Gly
NC_000007.13:g.117243741T>G
NM_000492.3:c.2813T>G

Protein change:

V938G

Links:

dbSNP: rs193922511

NCBI 1000 Genomes Browser:

rs193922511

Molecular consequence:

NM_000492.4:c.2813T>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
SCV001177641	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 10, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17329263, 28830496, 9272157 Citation Link,
SCV001576038	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 16, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9272157, 17329263, 28603918, 32777524, 36437957, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001177641

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jun 10, 2024)

germline

clinical testing

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

Citation Link,

SCV001576038

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 16, 2024)

germline

clinical testing

PubMed (6)
[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

What can the CF registry tell us about rare CFTR-mutations? A Belgian study.

De Wachter E, Thomas M, Wanyama SS, Seneca S, Malfroot A.

Orphanet J Rare Dis. 2017 Aug 22;12(1):142. doi: 10.1186/s13023-017-0694-1.

PubMed [citation]

PMID:: 28830496
PMCID:: PMC5567473

Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens.

Dörk T, Dworniczak B, Aulehla-Scholz C, Wieczorek D, Böhm I, Mayerova A, Seydewitz HH, Nieschlag E, Meschede D, Horst J, Pander HJ, Sperling H, Ratjen F, Passarge E, Schmidtke J, Stuhrmann M.

Hum Genet. 1997 Sep;100(3-4):365-77.

PubMed [citation]

PMID:: 9272157

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV001177641.5

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

Description

The p.V938G variant (also known as c.2813T>G), located in coding exon 17 of the CFTR gene, results from a T to G substitution at nucleotide position 2813. The valine at codon 938 is replaced by glycine, an amino acid with dissimilar properties. This variant was identified in two individuals; one individual was homozygous and presented with congenital unilateral absence of the vas deferens (CUAVD) and asthma bronchiale. The other individual was heterozygous for this variant as well as a frameshift alteration and presented with congenital bilateral absence of the vas deferens (CBAVD) and a borderline sweat chloride level; the phase of these alterations was not provided (Dörk T et al. Hum. Genet. 1997 Sep; 100(3-4):365-77). In another study, this variant was observed in one individual with CBAVD and a gross deletion (Ratbi I et al. Hum. Reprod. 2007 May;22(5):1285-91). 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 available evidence, 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, SCV001576038.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 938 of the CFTR protein (p.Val938Gly). This variant is present in population databases (rs193922511, gnomAD 0.003%). This missense change has been observed in individuals with cystic fibrosis, unilateral congenital absence of the vas deferens, or bilateral absence of the vas deferens (PMID: 9272157, 17329263, 28603918). ClinVar contains an entry for this variant (Variation ID: 35850). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFTR protein function with a negative predictive value of 80%. This variant disrupts the p.Val938 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 9272157, 17329263, 28603918, 32777524, 36437957), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as 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: Oct 13, 2024

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