NM_000498.3(CYP11B2):c.1343G>A (p.Arg448His) AND Corticosterone methyloxidase type 2 deficiency

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 1, 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:: RCV001160466.5

Allele description [Variation Report for NM_000498.3(CYP11B2):c.1343G>A (p.Arg448His)]

NM_000498.3(CYP11B2):c.1343G>A (p.Arg448His)

Genes:

LOC106799834:CYP11B2 recombination region [Gene]
CYP11B2:cytochrome P450 family 11 subfamily B member 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q24.3

Genomic location:

Preferred name:

NM_000498.3(CYP11B2):c.1343G>A (p.Arg448His)

HGVS:

NC_000008.11:g.142912585C>T
NG_008374.1:g.10259G>A
NG_046133.1:g.9228C>T
NM_000498.3:c.1343G>AMANE SELECT
NP_000489.3:p.Arg448His
NC_000008.10:g.143994001C>T

Protein change:

R448H

Links:

dbSNP: rs1311444460

NCBI 1000 Genomes Browser:

rs1311444460

Molecular consequence:

NM_000498.3:c.1343G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Corticosterone methyloxidase type 2 deficiency
Synonyms:: 18-OXIDASE DEFICIENCY; ALDOSTERONE DEFICIENCY DUE TO DEFICIENCY OF STEROID 18-OXIDASE; ALDOSTERONE DEFICIENCY II; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012524; MedGen: C3463917; Orphanet: 427; OMIM: 610600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001322270	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	Citation Link,
SCV002573300	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33098647, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001322270

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

Citation Link,

SCV002573300

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 1, 2022)

germline

clinical testing

PubMed (2)
[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	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular Analysis of the CYP11B2 Gene in 62 Patients with Hypoaldosteronism Due to Aldosterone Synthase Deficiency.

Merakou C, Fylaktou I, Sertedaki A, Dracopoulou M, Voutetakis A, Efthymiadou A, Christoforidis A, Dacou-Voutetakis C, Chrysis D, Kanaka-Gantenbein C.

J Clin Endocrinol Metab. 2021 Jan 1;106(1):e182-e191. doi: 10.1210/clinem/dgaa765.

PubMed [citation]

PMID:: 33098647

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

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001322270.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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

From 3billion, SCV002573300.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.81). A different missense change at the same codon (p.Arg448Cys) has been reported to be associated with CYP11B2-related disorder (PMID: 33098647). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance 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	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Apr 6, 2024

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