VCV000002263.19 - ClinVar

NM_000101.4(CYBA):c.214T>C (p.Tyr72His)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(14)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000101.4(CYBA):c.214T>C (p.Tyr72His)

Variation ID: 2263 Accession: VCV000002263.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q24.2 16: 88646828 (GRCh38) [ NCBI UCSC ] 16: 88713236 (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	Oct 2, 2016	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000101.4:c.214T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000092.2:p.Tyr72His	missense
NM_000101.2:c.214T>C
NC_000016.10:g.88646828A>G
NC_000016.9:g.88713236A>G
NG_007291.1:g.9222T>C
LRG_52:g.9222T>C
	P13498:p.Tyr72His

... more HGVS ... less HGVS

Protein change

Y72H

Other names

CYBA, HIS72TYR, 242C-T
H72Y

Canonical SPDI

NC_000016.10:88646827:A:G

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

loss_of_function_variant; Sequence Ontology [ SO:0002054]

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.

0.33566 (A)

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

Trans-Omics for Precision Medicine (TOPMed) 0.64302

The Genome Aggregation Database (gnomAD) 0.64973

1000 Genomes Project 30x 0.65881

1000 Genomes Project 0.66434

Exome Aggregation Consortium (ExAC) 0.69083

The Genome Aggregation Database (gnomAD), exomes 0.69770

Links

ClinGen: CA115456 UniProtKB: P13498#VAR_005122 OMIM: 608508.0008 dbSNP: rs4673 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.
CYBA		-	-	GRCh38 GRCh37	457	544

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.
CYBA POLYMORPHISM	Benign (1)	no assertion criteria provided	Jul 1, 2009	RCV000002351.4
not specified	Benign (5)	criteria provided, multiple submitters, no conflicts	Jan 24, 2024	RCV000249071.11
Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative	Benign (3)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000989646.8
Very early onset inflammatory bowel disease	Likely pathogenic (1)	no assertion criteria provided	Nov 6, 2018	RCV000736011.1
Chronic granulomatous disease	Benign (1)	no assertion criteria provided	Nov 18, 2019	RCV001826406.1
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	Mar 3, 2015	RCV001723534.4

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.
Benign (Dec 16, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002051157.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Comment: Variant summary: CYBA c.214T>C (p.Tyr72His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more) Variant summary: CYBA c.214T>C (p.Tyr72His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.7 in 250626 control chromosomes, suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 1139 fold of the estimated maximal expected allele frequency for a pathogenic variant in CYBA causing Chronic Granulomatous Disease phenotype (0.00061), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.214T>C in individuals affected with Chronic Granulomatous Disease and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed the clinical significance of this variant after 2014: four have classified the variant as benign and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as benign. (less)
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001950471.2 First in ClinVar: Oct 02, 2021 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 30709874, 17383305, 21884584, 18799874, 19689263, 11023926, 15078863, 23821607, 22396743, 23409188, 25095657, 23040216, 9445163, 24339896, 24392120, 29132304, … (more) This variant is associated with the following publications: (PMID: 30709874, 17383305, 21884584, 18799874, 19689263, 11023926, 15078863, 23821607, 22396743, 23409188, 25095657, 23040216, 9445163, 24339896, 24392120, 29132304, 29454792) (less)
Benign (Jan 24, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan Accession: SCV004232923.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Comment: This variant is classified as Benign based on local population frequency. This variant was detected in 93% of patients studied by a panel of primary … (more) This variant is classified as Benign based on local population frequency. This variant was detected in 93% of patients studied by a panel of primary immunodeficiencies. Number of patients: 88. Only high quality variants are reported. (less) Number of individuals with the variant: 88 Age: <18 years Sex: mixed
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001727890.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000302283.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001140177.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Benign (Jun 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001737969.1 First in ClinVar: Jun 24, 2021 Last updated: Jun 24, 2021	Sex: mixed
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005249677.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Jul 01, 2009)	no assertion criteria provided Method: literature only	CYBA POLYMORPHISM Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022509.3 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (4) PubMed: 3368442‚ 9445163‚ 10440830‚ 19388116 Comment on evidence: Parkos et al. (1988) identified a 242C-T polymorphism (rs4673) in exon 4 of the CYBA gene, leading to a his72-to-tyr (H72Y) substitution. Data on its … (more) Parkos et al. (1988) identified a 242C-T polymorphism (rs4673) in exon 4 of the CYBA gene, leading to a his72-to-tyr (H72Y) substitution. Data on its frequency in Japanese (Inoue et al., 1998) and U.S. (Li et al., 1999) populations have been reported. Bedard et al. (2009) noted that the 242C-T SNP is also referred to as 214T-C (Y72H) based on numbering from the ATG codon. Reactive Oxygen Species Generation Bedard et al. (2009) analyzed 7 CYBA polymorphisms and NOX2-dependent reactive oxygen species (ROS) generation in 50 unrelated healthy Caucasian individuals. The authors identified 11 haplotypes, which could be grouped into 7 haplogroups. Only 1 haplogroup, designated 'C' and containing the 214T-C, 521T-C (rs1049254, 549C-T, V174A), and the 3-prime UTR 24G-A (rs1049255, 640A-G) SNPs, had a significant effect on ROS production, showing markedly reduced ROS generation compared to other haplotypes. Although functional analysis demonstrated significantly reduced reporter gene activity with the A allele of the 3-prime UTR SNP 24G-A compared to the G allele (p = 0.0055), haplotype analysis indicated that the observed effect on ROS production was due to the strong contribution of haplotype C. Bedard et al. (2009) suggested that inconsistencies found in published reports might be due to the analysis of individual SNPs rather than haplotypes. (less)
Likely pathogenic (Nov 06, 2018)	no assertion criteria provided Method: research	Very early onset inflammatory bowel disease (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Institute of Clinical Molecular Biology, Kiel University Accession: SCV000864164.1 First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019	Publications: PubMed (1) PubMed: 30709874
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001744814.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001932837.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (Nov 18, 2019)	no assertion criteria provided Method: clinical testing	Chronic granulomatous disease Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002089439.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
not provided (-)	no classification provided Method: phenotyping only	Not Provided Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV002074602.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022	Comment: Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. (less) Clinical Features: Phenotypic abnormality (present) Indication for testing: Diagnostic Age: 40-49 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2020-04-27 Testing laboratory interpretation: Benign
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Comment:

Variant summary: CYBA c.214T>C (p.Tyr72His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.7 in 250626 control chromosomes, suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 1139 fold of the estimated maximal expected allele frequency for a pathogenic variant in CYBA causing Chronic Granulomatous Disease phenotype (0.00061), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.214T>C in individuals affected with Chronic Granulomatous Disease and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed the clinical significance of this variant after 2014: four have classified the variant as benign and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as benign.

Comment:

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
loss_of_function_variant (SO:0002054)	Method not provided	Result not provided	Institute of Clinical Molecular Biology, Kiel University Accession: SCV000864164.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Missense variants in NOX1 and p22phox in a case of very-early-onset inflammatory bowel disease are functionally linked to NOD2.	Lipinski S	Cold Spring Harbor molecular case studies	2019	PMID: 30709874
Three common polymorphisms in the CYBA gene form a haplotype associated with decreased ROS generation.	Bedard K	Human mutation	2009	PMID: 19388116
Relationship of the C242T p22phox gene polymorphism to angiographic coronary artery disease and endothelial function.	Li A	American journal of medical genetics	1999	PMID: 10440830
Polymorphism of the NADH/NADPH oxidase p22 phox gene in patients with coronary artery disease.	Inoue N	Circulation	1998	PMID: 9445163
Primary structure and unique expression of the 22-kilodalton light chain of human neutrophil cytochrome b.	Parkos CA	Proceedings of the National Academy of Sciences of the United States of America	1988	PMID: 3368442

Text-mined citations for rs4673 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000101.4(CYBA):c.214T>C (p.Tyr72His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs4673 ...