NM_000492.4(CFTR):c.377G>C (p.Gly126Ala) AND Cystic fibrosis

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 17, 2021
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:: RCV001970527.8

Allele description [Variation Report for NM_000492.4(CFTR):c.377G>C (p.Gly126Ala)]

NM_000492.4(CFTR):c.377G>C (p.Gly126Ala)

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.377G>C (p.Gly126Ala)

HGVS:

NC_000007.14:g.117531002G>C
NG_016465.4:g.70219G>C
NM_000492.4:c.377G>CMANE SELECT
NP_000483.3:p.Gly126Ala
LRG_663t1:c.377G>C
LRG_663:g.70219G>C
NC_000007.13:g.117171056G>C
NM_000492.3:c.377G>C

Protein change:

G126A

Links:

dbSNP: rs397508609

NCBI 1000 Genomes Browser:

rs397508609

Molecular consequence:

NM_000492.4:c.377G>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

Recent activity

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Homo sapiens glycogen synthase kinase 3 beta (GSK3B), mRNA
Homo sapiens glycogen synthase kinase 3 beta (GSK3B), mRNA
gi|4504162|ref|NM_002093.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002255154	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002620438	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Feb 17, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002255154

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 7, 2021)

germline

clinical testing

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

SCV002620438

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Feb 17, 2021)

germline

clinical testing

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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Molecular Structure of the Human CFTR Ion Channel.

Liu F, Zhang Z, Csanády L, Gadsby DC, Chen J.

Cell. 2017 Mar 23;169(1):85-95.e8. doi: 10.1016/j.cell.2017.02.024.

PubMed [citation]

PMID:: 28340353

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002255154.3

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

Description

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. This variant disrupts the p.Gly126 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23974870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CFTR-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 126 of the CFTR protein (p.Gly126Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine.

#	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, SCV002620438.2

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

Description

The p.G126A variant (also known as c.377G>C), located in coding exon 4 of the CFTR gene, results from a G to C substitution at nucleotide position 377. The glycine at codon 126 is replaced by alanine, an amino acid with similar properties. 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 internal structural analysis, this variant does not decrease structural stability (Liu F et al. Cell, 2017 03;169:85-95.e8). Since supporting evidence is limited at this time, 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

Last Updated: Sep 29, 2024

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