NM_000492.4(CFTR):c.3095A>G (p.Tyr1032Cys) AND Cystic fibrosis

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Dec 31, 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:: RCV000029516.33

Allele description [Variation Report for NM_000492.4(CFTR):c.3095A>G (p.Tyr1032Cys)]

NM_000492.4(CFTR):c.3095A>G (p.Tyr1032Cys)

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
LOC111674472:DNase I hypersensitive sites in introns 16 and 17a of CFTR [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.3095A>G (p.Tyr1032Cys)

HGVS:

NC_000007.14:g.117610625A>G
NG_016465.4:g.149842A>G
NG_056128.2:g.3679A>G
NM_000492.4:c.3095A>GMANE SELECT
NP_000483.3:p.Tyr1032Cys
NP_000483.3:p.Tyr1032Cys
LRG_663t1:c.3095A>G
LRG_663:g.149842A>G
LRG_663p1:p.Tyr1032Cys
NC_000007.13:g.117250679A>G
NM_000492.3:c.3095A>G

Protein change:

Y1032C

Links:

dbSNP: rs144055758

NCBI 1000 Genomes Browser:

rs144055758

Molecular consequence:

NM_000492.4:c.3095A>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
SCV000052167	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 28, 2020)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 9272157, 17329263, 16801189, 12133923, 21520337, 21538969, 19318035, 19406970, 23883480, 27171515, 28603918, 29805046, 30046002, 31776420, 31808782, 30888834 Citation Link,
SCV000916185	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Sep 6, 2018)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 19318035, 16801189, 12133923, 21538969, 17329263, 23883480, 9272157 Citation Link,
SCV001179821	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 12133923, 16801189, 21538969, 23883480, 25910067, 26755536, 27171515, 28603918, 29805046, 30046002, 9272157 Citation Link,
SCV001577665	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 31, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 9272157, 17329263, 19406970, 21520337, 23883480, 29805046, 28492532
SCV002583261	Baylor Genetics	no assertion criteria provided	Pathogenic	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9272157, 23883480, 27171515, 29805046

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Nanomolar-potency 'co-potentiator' therapy for cystic fibrosis caused by a defined subset of minimal function CFTR mutants.

Phuan PW, Tan JA, Rivera AA, Zlock L, Nielson DW, Finkbeiner WE, Haggie PM, Verkman AS.

Sci Rep. 2019 Nov 27;9(1):17640. doi: 10.1038/s41598-019-54158-2.

PubMed [citation]

PMID:: 31776420
PMCID:: PMC6881293

Determining the pathogenicity of CFTR missense variants: Multiple comparisons of in silico predictors and variant annotation databases.

Michels M, Matte U, Fraga LR, Mancuso ACB, Ligabue-Braun R, Berneira EFR, Siebert M, Sanseverino MTV.

Genet Mol Biol. 2019 Jul-Sep;42(3):560-570. doi: 10.1590/1678-4685-GMB-2018-0148. Epub 2019 Nov 14.

PubMed [citation]

PMID:: 31808782
PMCID:: PMC6905453

See all PubMed Citations (20)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052167.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

Variant summary: CFTR c.3095A>G (p.Tyr1032Cys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 1.6e-05 in 251624 control chromosomes. c.3095A>G has been reported in the literature and in multiple databases in compound heterozygous individuals with varying clinical consequences, ranging from Congenital Bilateral Absence of the Vas Deferens (CBAVD) to Cystic Fibrosis (usually with pancreatic sufficiency). There are 16 patients listed with this variant in the CFTR2 database, 27% of which are reported as pancreatic insufficient. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, indicating that the variant results in 10%-<30% of normal CFTR activity (e.g. Raraigh_2018, Han_2018, McCague_2019). Five other ClinVar submitters (evaluation after 2014) cite 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 Illumina Laboratory Services, Illumina, SCV000916185.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The CFTR c.3095A>G (p.Tyr1032Cys) missense variant has been reported in four probands in seven different studies (DÃ¶rk et al. 1997; Corbetta et al. 2002; Padoan et al. 2006; Ratbi et al. 2007; Seia et al. 2009; Ren et al. 2011; Leonardi et al. 2013). The p.Tyr1032Cys variant was commonly reported in combination with the well-described severe pathogenic variant, p.Phe508del. However, only two of the seven probands had a clearly positive chloride sweat test and would be considered to have classic CF (DÃ¶rk et al. 1997; Seia et al. 2009). The p.Tyr1032Cys variant is associated with a mild phenotype (Leonardi et al. 2013). The p.Tyr1032Cys variant presented with various atypical CF phenotypes - persistent hypertrypsinogenaemia and a borderline chloride sweat test, acute pancreatitis at age six with a borderline chloride sweat test, and congenital bilateral absence of the vas deferens (CBAVD) and recurrent bronchitis (DÃ¶rk et al. 1997, Padoan et al. 2006, Ratbi et al. 2007; Seia et al. 2009; Ren et al. 2011; Leonardi et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.000036 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Tyr1032Cys variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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, SCV001179821.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The p.Y1032C variant (also known as c.3095A>G), located in coding exon 19 of the CFTR gene, results from an A to G substitution at nucleotide position 3095. The tyrosine at codon 1032 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was described in 2 individuals in conjunction with p.F508del (phase unknown); one individual had a positive newborn screen and indeterminate sweat chloride levels while the other had congenital bilateral absence of the vas deferens (CBAVD) and recurrent bronchitis (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77; Ren CL et al. Pediatr. Pulmonol., 2011 Nov;46:1079-84). In a Caucasian female who presented with a positive newborn screen, borderline sweat tests, and pancreatic sufficiency who went on to develop acute pancreatitis, this variant was in trans with p.F508del and p.R1438W (Leonardi S et al. J Med Case Rep, 2013 Jul;7:188). In CFBE cells, this variant showed reduced CFTR function compared to wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077; Han ST et al. JCI Insight, 2018 Jul;3(14):pii 121159). The p.Y1032C alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). 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 majority of available evidence to date, this variant is likely to be 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, SCV001577665.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1032 of the CFTR protein (p.Tyr1032Cys). This variant is present in population databases (rs144055758, gnomAD 0.004%). This missense change has been observed in individuals with congenital absence of the vas deferens or cystic fibrosis (PMID: 9272157, 17329263, 19406970, 21520337, 23883480). ClinVar contains an entry for this variant (Variation ID: 35861). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046). 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 Genome Diagnostics Laboratory, The Hospital for Sick Children, SCV002507385.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV002583261.1

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

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002507385	Genome Diagnostics Laboratory, The Hospital for Sick Children	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Mar 19, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002507385

Genome Diagnostics Laboratory, The Hospital for Sick Children

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 19, 2021)

germline

clinical testing

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

Last Updated: Oct 13, 2024

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