VCV000054018.24 - ClinVar

NM_000492.4(CFTR):c.595C>T (p.His199Tyr)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Pathogenic

for Cystic fibrosis

Classification is based on the expert panel submission

Mar 2017 by CFTR2

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000492.4(CFTR):c.595C>T (p.His199Tyr)

Variation ID: 54018 Accession: VCV000054018.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117535263 (GRCh38) [ NCBI UCSC ] 7: 117175317 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 24, 2015	Feb 25, 2025	Mar 17, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.595C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.His199Tyr	missense
NC_000007.14:g.117535263C>T
NC_000007.13:g.117175317C>T
NG_016465.4:g.74480C>T
LRG_663:g.74480C>T
LRG_663t1:c.595C>T	LRG_663p1:p.His199Tyr
	P13569:p.His199Tyr

... more HGVS ... less HGVS

Protein change

H199Y

Other names

Canonical SPDI

NC_000007.14:117535262:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA328129 UniProtKB: P13569#VAR_000134 dbSNP: rs121908802 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CFTR		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	4081	5549

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cystic fibrosis	Pathogenic (8)	reviewed by expert panel	Mar 17, 2017	RCV000056399.19
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 19, 2017	RCV000755925.8
Bronchiectasis with or without elevated sweat chloride 1 Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Hereditary pancreatitis	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763155.2
CFTR-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 17, 2017	RCV001831798.1
Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis	Pathogenic (1)	criteria provided, single submitter	-	RCV001004441.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 17, 2017) C Contributing to aggregate classification	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013)) Method: research	Cystic fibrosis Affected status: yes Allele origin: germline	CFTR2 Study: CFTR2 Accession: SCV000071504.4 First in ClinVar: Oct 18, 2013 Last updated: Jan 06, 2018	Other databases https://cftr2.org https://cftr2.org

Pathogenic (Sep 19, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	Not Provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000883601.1 First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001163486.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020

Pathogenic (Sep 07, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV002570341.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Comment: Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.

Likely pathogenic (Sep 30, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000487061.2 First in ClinVar: Mar 24, 2015 Last updated: Dec 24, 2022	Publications: PubMed (1) PubMed: 23974870

Pathogenic (Jun 13, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697036.1 First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018	Publications: PubMed (8) PubMed: 17331079‚ 9439669‚ 16963320‚ 7525450‚ 26708955‚ 23974870‚ 8844213‚ 15858154 Comment: Variant summary: The CFTR c.595C>T (p.His199Tyr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution that lies within the ABC transporter … (more) Variant summary: The CFTR c.595C>T (p.His199Tyr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution that lies within the ABC transporter type 1, transmembrane domain (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent from the large control database ExAC (0/121410 control chromosomes). The variant has been identified in numerous cystic fibrosis patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. (less)

Pathogenic (Oct 31, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Bronchiectasis with or without elevated sweat chloride 1 Cystic fibrosis Congenital bilateral aplasia of vas deferens from CFTR mutation Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893742.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30

Pathogenic (Jan 29, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017)) Method: curation	cystic fibrosis Affected status: yes Allele origin: germline	CFTR-France Accession: SCV001169307.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Publications: PubMed (1) PubMed: 28603918

Pathogenic (May 24, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002656482.3 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 15084222‚ 23974870‚ 7525450 Comment: The p.H199Y pathogenic mutation (also known as c.595C>T), located in coding exon 6 of the CFTR gene, results from a C to T substitution at … (more) The p.H199Y pathogenic mutation (also known as c.595C>T), located in coding exon 6 of the CFTR gene, results from a C to T substitution at nucleotide position 595. The histidine at codon 199 is replaced by tyrosine, an amino acid with similar properties. This mutation was reported in multiple individuals with cystic fibrosis and a second mutation in trans; in vitro studies using HeLa cells expressing this mutation showed a severe processing defect of the CFTR protein (Sosnay PR et al, Nat. Genet. 2013 Oct; 45(10):1160-7). In addition, a disease-causing alteration, p.H199R, has been described in the same codon (D'Apice MR et al, BMC Med. Genet. 2004 Apr; 5:8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)

Pathogenic (Dec 15, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001580660.5 First in ClinVar: May 10, 2021 Last updated: Feb 25, 2025	Publications: PubMed (8) PubMed: 7525450‚ 10798368‚ 12007216‚ 15858154‚ 18456578‚ 27143075‚ 28608624‚ 23974870 Comment: This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 199 of the CFTR protein (p.His199Tyr). … (more) This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 199 of the CFTR protein (p.His199Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cystic fibrosis (PMID: 7525450, 10798368, 12007216, 15858154, 18456578, 27143075, 28608624). ClinVar contains an entry for this variant (Variation ID: 54018). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 23974870). For these reasons, this variant has been classified as Pathogenic. (less)

Pathogenic (Jun 22, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005849438.1 First in ClinVar: Feb 25, 2025 Last updated: Feb 25, 2025	Comment: The missense c.595C>T (p.His199Tyr) variant in the CFTR gene has been observed in individuals with cystic fibrosis (Castellani, C et al.,2008). Experimental studies have shown … (more) The missense c.595C>T (p.His199Tyr) variant in the CFTR gene has been observed in individuals with cystic fibrosis (Castellani, C et al.,2008). Experimental studies have shown that this missense change affects CFTR function (Sosnay, Patrick R et al., 2013). This variant has been reported to the ClinVar database as Pathogenic with a status of reviewed by expert panel. The amino acid Histidine at position 199 is changed to a Tyrosine changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic with a status of reviewed by expert panel. Multiple lines of computational evidence (Polyphen - Damaging, SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid Histidine in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Abnormality of the pancreas (present) Comment on clinical features: Current clinical features: Severe steatorrhea, initally 10-12 episodes per day, now 4-5 episodes per day. Age of onset: 6 months of age Consanguinity: Present (3rd degree consanguinity) Antenatal/ Birth history: B wt-3.5 kgs On examination: Ht- 82cm, Wt- 9.4kgs (<1%ile) Investigation: Hb- 10.8, TC-14.5, Alb- 4.6,Na- 140, K+-4.7, HCO3-20 Possible clinical diagnosis: ?Steatorrhea, Chronic/congenital diarrhea, Pancreatic insufficiency, FTT

Pathogenic (Mar 17, 2017) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	CFTR-related disorders Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002078116.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022

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Comment:

Variant summary: The CFTR c.595C>T (p.His199Tyr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution that lies within the ABC transporter type 1, transmembrane domain (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent from the large control database ExAC (0/121410 control chromosomes). The variant has been identified in numerous cystic fibrosis patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

The p.H199Y pathogenic mutation (also known as c.595C>T), located in coding exon 6 of the CFTR gene, results from a C to T substitution at nucleotide position 595. The histidine at codon 199 is replaced by tyrosine, an amino acid with similar properties. This mutation was reported in multiple individuals with cystic fibrosis and a second mutation in trans; in vitro studies using HeLa cells expressing this mutation showed a severe processing defect of the CFTR protein (Sosnay PR et al, Nat. Genet. 2013 Oct; 45(10):1160-7). In addition, a disease-causing alteration, p.H199R, has been described in the same codon (D'Apice MR et al, BMC Med. Genet. 2004 Apr; 5:8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 199 of the CFTR protein (p.His199Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cystic fibrosis (PMID: 7525450, 10798368, 12007216, 15858154, 18456578, 27143075, 28608624). ClinVar contains an entry for this variant (Variation ID: 54018). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 23974870). For these reasons, this variant has been classified as Pathogenic.

Comment:

The missense c.595C>T (p.His199Tyr) variant in the CFTR gene has been observed in individuals with cystic fibrosis (Castellani, C et al.,2008). Experimental studies have shown that this missense change affects CFTR function (Sosnay, Patrick R et al., 2013). This variant has been reported to the ClinVar database as Pathogenic with a status of reviewed by expert panel. The amino acid Histidine at position 199 is changed to a Tyrosine changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic with a status of reviewed by expert panel. Multiple lines of computational evidence (Polyphen - Damaging, SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid Histidine in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Four case reports of Chinese cystic fibrosis patients and literature review.	Xu J	Pediatric pulmonology	2017	PMID: 28608624
[Molecular diagnosis of two Chinese cystic fibrosis children and literature review].	Xu BP	Zhonghua er ke za zhi = Chinese journal of pediatrics	2016	PMID: 27143075
The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing.	Schrijver I	The Journal of molecular diagnostics : JMD	2016	PMID: 26708955
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.	Sosnay PR	Nature genetics	2013	PMID: 23974870
Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice.	Castellani C	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2008	PMID: 18456578
Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry.	Alonso MJ	Annals of human genetics	2007	PMID: 17331079
CFTR gene analysis in Latin American CF patients: heterogeneous origin and distribution of mutations across the continent.	Pérez MM	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2007	PMID: 16963320
Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum.	Schrijver I	The Journal of molecular diagnostics : JMD	2005	PMID: 15858154
Molecular analysis using DHPLC of cystic fibrosis: increase of the mutation detection rate among the affected population in Central Italy.	D'Apice MR	BMC medical genetics	2004	PMID: 15084222
Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening.	Bobadilla JL	Human mutation	2002	PMID: 12007216
Spectrum of CFTR mutations in Mexican cystic fibrosis patients: identification of five novel mutations (W1098C, 846delT, P750L, 4160insGGGG and 297-1G-->A).	Orozco L	Human genetics	2000	PMID: 10798368
High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes.	Casals T	Human genetics	1997	PMID: 9439669
Haplotype analysis of 94 cystic fibrosis mutations with seven polymorphic CFTR DNA markers.	Morral N	Human mutation	1996	PMID: 8844213
Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients.	Dörk T	Human genetics	1994	PMID: 7525450
https://cftr2.org	-	-	-	-
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Text-mined citations for rs121908802 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 17, 2025

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.595C>T (p.His199Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908802 ...