NM_000397.4(CYBB):c.1060C>T (p.His354Tyr) AND Granulomatous disease, chronic, X-linked

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 4, 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:: RCV003153062.3

Allele description [Variation Report for NM_000397.4(CYBB):c.1060C>T (p.His354Tyr)]

NM_000397.4(CYBB):c.1060C>T (p.His354Tyr)

Gene:

CYBB:cytochrome b-245 beta chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.4

Genomic location:

Preferred name:

NM_000397.4(CYBB):c.1060C>T (p.His354Tyr)

HGVS:

NC_000023.11:g.37804039C>T
NG_009065.1:g.29023C>T
NM_000397.4:c.1060C>TMANE SELECT
NP_000388.2:p.His354Tyr
NP_000388.2:p.His354Tyr
LRG_53t1:c.1060C>T
LRG_53:g.29023C>T
LRG_53p1:p.His354Tyr
NC_000023.10:g.37663292C>T
NM_000397.3:c.1060C>T

Protein change:

H354Y

Molecular consequence:

NM_000397.4:c.1060C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Granulomatous disease, chronic, X-linked
Synonyms:: CYTOCHROME b-NEGATIVE GRANULOMATOUS DISEASE, CHRONIC, X-LINKED; GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, SOMATIC MOSAIC
Identifiers:: MONDO: MONDO:0010600; MedGen: C1844376; Orphanet: 379; OMIM: 306400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003841809	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 23, 2023)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10089913, 20729109, 25741868
SCV004331917	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 4, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10089913, 20729109, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003841809

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 23, 2023)

unknown

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004331917

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 4, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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	yes	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

Uncommon missense and splice mutations and resulting biochemical phenotypes in German patients with X-linked chronic granulomatous disease.

Roesler J, Heyden S, Burdelski M, Schäfer H, Kreth HW, Lehmann R, Paul D, Marzahn J, Gahr M, Rösen-Wolff A.

Exp Hematol. 1999 Mar;27(3):505-11.

PubMed [citation]

PMID:: 10089913

See all PubMed Citations (4)

Details of each submission

From 3billion, SCV003841809.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.89). Different missense changes at the same codon (p.His354Arg, p.His354Pro) have been reported to be associated with CYBB related disorder (PMID: 10089913, 20729109). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004331917.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 354 of the CYBB protein (p.His354Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CYBB-related conditions. ClinVar contains an entry for this variant (Variation ID: 2444264). 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 CYBB protein function. This variant disrupts the p.His354 amino acid residue in CYBB. Other variant(s) that disrupt this residue have been observed in individuals with CYBB-related conditions (PMID: 10089913, 20729109), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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