NM_000492.4(CFTR):c.3095A>G (p.Tyr1032Cys) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Dec 7, 2022
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:: RCV000591587.25

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]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000603056	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Jun 18, 2018)	germline	clinical testing	Citation Link,
SCV000700725	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Likely pathogenic (Jun 11, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12133923, 17329263, 19406970, 21520337, 23883480, 9272157 Citation Link,
SCV001714242	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 20, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002047126	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely pathogenic (Dec 7, 2022)	unknown	clinical testing	PubMed (22) [See all records that cite these PMIDs] 23883480, 17329263, 19406970, 30046002, 29805046, 28603918, 27171515, 21538969, 21520337, 20059485, 19318035, 16801189, 12133923, 11504857, 9272157, 25910067, 31776420, 28736296, 26277102, 11883825, 17407485, 26467025
SCV002577129	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Sep 29, 2022)	germline	clinical testing	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	unknown	6	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

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

Early acute pancreatitis in a child with compound heterozygosis ∆F508/R1438W/Y1032C cystic fibrosis: a case report.

Leonardi S, Praticò AD, Rotolo N, Di Dio G, Lionetti E, La Rosa M.

J Med Case Rep. 2013 Jul 24;7:188. doi: 10.1186/1752-1947-7-188.

PubMed [citation]

PMID:: 23883480
PMCID:: PMC3750286

See all PubMed Citations (23)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603056.2

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

Description

The CFTR c.3095A>G; p.Tyr1032Cys variant (rs144055758) is reported in individuals with atypical cystic fibrosis (i.e. monosymptomatic disease) when in combination with a severe pathogenic variant (Dork 1997, Leonardi 2013, Ratbi 2007, Ren 2011). This variant has varying clinical consequences and is commonly associated with pancreatic sufficiency (CFTR2 database). It is reported as pathogenic or likely pathogenic in ClinVar (Variation ID: 35861), and is found in the general population at a low overall allele frequency of 0.002% (4/245758 alleles) in the Genome Aggregation Database. The tyrosine at codon 1032 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered pathogenic and likely to be a mild pathogenic variant. REFERENCES CFTR2 database: https://www.cftr2.org Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997 Sep;100(3-4):365-77. Leonardi S et al. Early acute pancreatitis in a child with compound heterozygosis F508/R1438W/Y1032C cystic fibrosis: a case report. J Med Case Rep. 2013 Jul 24;7:188. Ratbi I et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod. 2007 May;22(5):1285-91 Ren CL et al. Clinical outcomes in infants with cystic fibrosis transmembrane conductance regulator (CFTR) related metabolic syndrome. Pediatr Pulmonol. 2011 Nov;46(11):1079-84.

#	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 Eurofins Ntd Llc (ga), SCV000700725.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (6)

#	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		2	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001714242.2

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

Description

PM2, PM3, PS3

#	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		4	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002047126.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (22)

Description

In the published literature, the variant has been reported in individuals affected with Cystic Fibrosis or Cystic Fibrosis related disorders (CFRD) in the published literature (PMID: 27171515 (2016), 26277102 (2015), 25910067 (2015), 21538969 (2011), 21520337 (2011), 19406970 (2009)). In addition, this variant has been shown to affect CFTR chloride conductance function (PMID: 30046002 (2018), 29805046 (2018)). Based on the available information, the variant is classified as likely pathogenic.

#	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 GeneDx, SCV002577129.2

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect (Han 2018, Raraigh 2018); Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 12133923, 28603918, 9272157, 27171515, 30046002, 11883825, 16801189, 19318035, 30888834, 21538969, 17407489, 21520337, 29805046, 17329263, 23883480, 35523714, 35451201, Tosco[letter]2022, 35913788)

#	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

Last Updated: Oct 13, 2024

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