NM_000492.4(CFTR):c.3389G>C (p.Gly1130Ala) AND Cystic fibrosis

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Nov 21, 2023
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:: RCV000577261.4

Allele description [Variation Report for NM_000492.4(CFTR):c.3389G>C (p.Gly1130Ala)]

NM_000492.4(CFTR):c.3389G>C (p.Gly1130Ala)

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.3389G>C (p.Gly1130Ala)

HGVS:

NC_000007.14:g.117614634G>C
NG_016465.4:g.153851G>C
NM_000492.4:c.3389G>CMANE SELECT
NP_000483.3:p.Gly1130Ala
NP_000483.3:p.Gly1130Ala
LRG_663t1:c.3389G>C
LRG_663:g.153851G>C
LRG_663p1:p.Gly1130Ala
NC_000007.13:g.117254688G>C
NM_000492.3:c.3389G>C
p.Gly1130Ala

Protein change:

G1130A

Links:

dbSNP: rs397508550

NCBI 1000 Genomes Browser:

rs397508550

Molecular consequence:

NM_000492.4:c.3389G>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
SCV000679438	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]
SCV002614571	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 21, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15070876, 16126774, 25536748, 31005549, 32150665, 32357917 Citation Link,
SCV002938063	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 30, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15070876, 31005549, 32357917, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000679438

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]

SCV002614571

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Nov 21, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV002938063

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 30, 2021)

germline

clinical testing

PubMed (4)
[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	yes	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Gender-sensitive association of CFTR gene mutations and 5T allele emerging from a large survey on infertility.

Morea A, Cameran M, Rebuffi AG, Marzenta D, Marangon O, Picci L, Zacchello F, Scarpa M.

Mol Hum Reprod. 2005 Aug;11(8):607-14. Epub 2005 Aug 26.

PubMed [citation]

PMID:: 16126774

Clinical and prognostic importance of chromosomal abnormalities, Y chromosome microdeletions, and CFTR gene mutations in individuals with azoospermia or severe oligospermia.

Ocak Z, Üyetüork U, Dinçer MM.

Turk J Med Sci. 2014;44(2):347-51.

PubMed [citation]

PMID:: 25536748

See all PubMed Citations (7)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000679438.1

#	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 Ambry Genetics, SCV002614571.2

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

Description

The p.G1130A variant (also known as c.3389G>C), located in coding exon 21 of the CFTR gene, results from a G to C substitution at nucleotide position 3389. The glycine at codon 1130 is replaced by alanine, an amino acid with similar properties. This alteration has been described in patients with congenital bilateral absence of the vas deferens (CBAVD) in conjunction with other pathogenic mutation in CFTR; however, phase of the alterations was not specified (Dayangaç D et al. Hum Reprod, 2004 May;19:1094-100; Ocak Z et al. Turk J Med Sci, 2014;44:347-51). This alteration has also been reported in infertility cohorts (Morea A et al. Mol Hum Reprod, 2005 Aug;11:607-14; Chamayou S et al. BMC Med Genet, 2020 05;21:89), and in conjunction with a with pathogenic mutation in CFTR in an individual with no clinical diagnosis of cystic fibrosis and intermediate sweat chloride levels (Terlizzi V et al. J Cyst Fibros, 2019 07;18:484-490). 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 available evidence to date, this variant is unlikely to be causative of classic cystic fibrosis; however, its contribution to the development of a CFTR-related disorder is uncertain. This alteration is thus classified as a variant of unknown 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

From Invitae, SCV002938063.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glycine with alanine at codon 1130 of the CFTR protein (p.Gly1130Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs397508550, ExAC 0.02%). This variant has been observed in individual(s) with CFTR-related conditions and/or congenital absence of vas deferens (PMID: 15070876, 31005549, 32357917). ClinVar contains an entry for this variant (Variation ID: 53730). 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 disruptive. 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: May 1, 2024

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