NM_000492.4(CFTR):c.1651G>A (p.Gly551Ser) AND Cystic fibrosis

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Mar 17, 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:: RCV000007562.19

Allele description [Variation Report for NM_000492.4(CFTR):c.1651G>A (p.Gly551Ser)]

NM_000492.4(CFTR):c.1651G>A (p.Gly551Ser)

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.1651G>A (p.Gly551Ser)

HGVS:

NC_000007.14:g.117587805G>A
NG_016465.4:g.127022G>A
NG_056131.3:g.760G>A
NM_000492.4:c.1651G>AMANE SELECT
NP_000483.3:p.Gly551Ser
NP_000483.3:p.Gly551Ser
LRG_663t1:c.1651G>A
LRG_663:g.127022G>A
LRG_663p1:p.Gly551Ser
NC_000007.13:g.117227859G>A
NG_056131.1:g.129G>A
NM_000492.3:c.1651G>A
P13569:p.Gly551Ser

Protein change:

G551S; GLY551SER

Links:

PharmGKB: 1183960780; PharmGKB: 1183960780PA165950341; PharmGKB Clinical Annotation: 1183960780; UniProtKB: P13569#VAR_000180; OMIM: 602421.0037; dbSNP: rs121909013

NCBI 1000 Genomes Browser:

rs121909013

Molecular consequence:

NM_000492.4:c.1651G>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000027763	OMIM	no assertion criteria provided	Pathogenic (Dec 5, 1991)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000245884	CFTR2 - CFTR2	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013))	Pathogenic (Mar 17, 2017)	germline	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000485648	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jan 20, 2016)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 22293084, 11242048, 9379898, 7544788, 1722350, 7606851, 10798368, 1944451 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV001167249	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 16, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001360489	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 24, 2022)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 7544788, 7521937, 12007216, 11242048, 1284534, 10798368, 8741733, 9163660, 1722350, 7606851, 1944451, 19019741, 1382316, 11448786, 30888834 Citation Link,
SCV001581779	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 4, 2022)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 1944451, 7606851, 23974870, 11242048, 22293084, 1379413, 1695717, 8605891, 19734299, 28492532
SCV002704675	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 11, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 1382316, 1944451, 22293084, 7606851 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	research
not provided	germline	not provided	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutational analysis of the Saccharomyces cerevisiae ATP-binding cassette transporter protein Ycf1p.

Wemmie JA, Moye-Rowley WS.

Mol Microbiol. 1997 Aug;25(4):683-94.

PubMed [citation]

PMID:: 9379898

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

See all PubMed Citations (24)

Details of each submission

From OMIM, SCV000027763.2

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

Description

In 2 sisters with mild cystic fibrosis (CF; 219700), the offspring of second-cousin parents, Strong et al. (1991) found a G-to-A substitution at basepair 1783 resulting in substitution of a serine for a glycine residue at the highly conserved position of amino acid 551. The proposita was a 50-year-old woman with a chronic productive cough. She had frequent pulmonary infections. Her sweat electrolyte concentrations were borderline normal. The patient had 2 normal pregnancies and deliveries and raised these children while working as a truck inspector. The patient had a sister who died of respiratory failure at the age of 48. She had delivered 4 healthy children without difficulty, had no evidence of malabsorption, and was in good health until the age of 23 when she had an episode of hemoptysis. At that time she was reported to have digital clubbing and bronchiectasis on chest roentgenography. Several sweat tests were normal.

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

From CFTR2 - CFTR2, SCV000245884.2

#	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 Counsyl, SCV000485648.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

#	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, SCV001167249.1

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

Description

Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360489.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

Variant summary: CFTR c.1651G>A (p.Gly551Ser) results in a non-conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250911 control chromosomes. c.1651G>A has been reported in the literature in multiple individuals affected with Cystic Fibrosis in the homozygous and compound heterozygous state (examples: Orozco_1995, Strong_1991, McCague_2019). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that although the variant was found to have no effect on bicarbonate permeability or chloride transport, it did result in a negative effect in a number of other CFTR functions including activation of chloride conductance, probability of channel opening and biocarbonate transport (Tang_2009, Choi_2001, Wilkinson_1996, Anderson_1992, Drumm_1991). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001581779.3

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 551 of the CFTR protein (p.Gly551Ser). This variant is present in population databases (rs121909013, gnomAD 0.003%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 1944451, 7606851, 23974870). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as 1783G>A. ClinVar contains an entry for this variant (Variation ID: 7142). 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 expected to disrupt CFTR protein function. Experimental studies have shown that this missense change affects CFTR function (PMID: 11242048, 22293084). This variant disrupts the p.Gly551 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1379413, 1695717, 8605891, 19734299). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

From Ambry Genetics, SCV002704675.3

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

Description

The p.G551S pathogenic mutation (also known as c.1651G>A and 1783G>A), located in coding exon 12 of the CFTR gene, results from a G to A substitution at nucleotide position 1651. The glycine at codon 551 is replaced by serine, an amino acid with similar properties. This mutation was first described in two Caucasian siblings homozygous for this mutation with mild pulmonary symptoms, pancreatic sufficiency, and normal sweat chloride levels (Strong TV et al. N. Engl. J. Med., 1991 Dec;325:1630-4). This mutation has also been described in three Mexican siblings with mild pulmonary symptoms, pancreatic sufficiency, elevated sweat chloride levels, and the p.F508del mutation confirmed in trans (Orozco L et al. Clin. Genet., 1995 Feb;47:96-8). Codon 551 resides within nucleotide-binding domain 1 (NBD1) of the CFTR protein and in vitro functional studies have shown that the p.G551S mutation decreased chloride channel activity compared to the wild-type CFTR protein (Anderson MP et al. Science, 1992 Sep;257:1701-4; Yu H et al. J. Cyst. Fibros., 2012 May;11:237-45). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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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