NM_000492.4(CFTR):c.1630G>A (p.Gly544Ser) AND Cystic fibrosis

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Dec 4, 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:: RCV000671136.11

Allele description [Variation Report for NM_000492.4(CFTR):c.1630G>A (p.Gly544Ser)]

NM_000492.4(CFTR):c.1630G>A (p.Gly544Ser)

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
LOC111674475:CFTR intron 11 enhancer [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.1630G>A (p.Gly544Ser)

HGVS:

NC_000007.14:g.117587784G>A
NG_016465.4:g.127001G>A
NG_056131.3:g.739G>A
NM_000492.3:c.[1630G>A]
NM_000492.4:c.1630G>AMANE SELECT
NP_000483.3:p.Gly544Ser
NP_000483.3:p.Gly544Ser
LRG_663t1:c.1630G>A
LRG_663:g.127001G>A
LRG_663p1:p.Gly544Ser
NC_000007.13:g.117227838G>A
NM_000492.3:c.1630G>A
NM_000492.3:c.[1630G>A]
NM_000492.4:c.1630G>A

Protein change:

G544S

Links:

dbSNP: rs762224063

NCBI 1000 Genomes Browser:

rs762224063

Molecular consequence:

NM_000492.4:c.1630G>A - 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

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000796085	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Dec 7, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001412407	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 1, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10376575, 10923036, 20021716, 28492532
SCV002027422	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002073097	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002707591	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Dec 4, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10376575, 20021716, 8530001 Citation Link

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	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France.

Claustres M, Guittard C, Bozon D, Chevalier F, Verlingue C, Ferec C, Girodon E, Cazeneuve C, Bienvenu T, Lalau G, Dumur V, Feldmann D, Bieth E, Blayau M, Clavel C, Creveaux I, Malinge MC, Monnier N, Malzac P, Mittre H, Chomel JC, Bonnefont JP, et al.

Hum Mutat. 2000;16(2):143-56.

PubMed [citation]

PMID:: 10923036

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

See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000796085.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001412407.2

#	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 serine at codon 544 of the CFTR protein (p.Gly544Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs762224063, ExAC 0.05%). This missense change has been observed in individual(s) with cystic fibrosis or infertility (PMID: 10376575, 10923036, 20021716). ClinVar contains an entry for this variant (Variation ID: 555335). 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. 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

From Genome-Nilou Lab, SCV002027422.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV002073097.1

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

Description

The missense variant p.G544S in CFTR (NM_000492.4) has been reported previously in affected individuals with trypisinemia but no elevated sweat chloride as well as infertile men with oligospermia (Scotet V et al,Gallati S et al). The variant has been submitted to ClinVar as Uncertain Significance. The p.G544S variant is observed in an allele frequency of 0.05% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G544S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 544 of CFTR is conserved in all mammalian species. The nucleotide c.1630 in CFTR is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

#	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, SCV002707591.2

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

Description

The p.G544S variant (also known as c.1630G>A), located in coding exon 12 of the CFTR gene, results from a G to A substitution at nucleotide position 1630. The glycine at codon 544 is replaced by serine, an amino acid with similar properties. This alteration was described in the heterozygous state in a newborn with normal sweat test result at birth and four months old (Férec C et al. Hum. Genet., 1995 Nov;96:542-8). This alteration was reported in a male with idiopathic epididymal obstruction in conjunction with the 5T allele; however, the phase was not provided (Mak V et al. JAMA, 1999 Jun;281:2217-24). This alteration was also detected as heterozygous in 1/169 oligospermic men (Gallati S et al. Reprod Biomed Online, 2009 Nov;19:685-94). 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, 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

ClinVar

Relating variation to medicine