VCV002684168.2 - ClinVar

NM_000500.9(CYP21A2):c.1100G>A (p.Arg367His)

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.

(2)

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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000500.9(CYP21A2):c.1100G>A (p.Arg367His)

Variation ID: 2684168 Accession: VCV002684168.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p21.33 6: 32040566 (GRCh38) [ NCBI UCSC ] 6: 32008343 (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	Jan 26, 2024	Oct 8, 2024	Oct 15, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000500.9:c.1100G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000491.4:p.Arg367His	missense
NM_001128590.4:c.1010G>A	NP_001122062.3:p.Arg337His	missense
NM_001368143.2:c.695G>A	NP_001355072.1:p.Arg232His	missense
NM_001368144.2:c.695G>A	NP_001355073.1:p.Arg232His	missense
NC_000006.12:g.32040566G>A
NC_000006.11:g.32008343G>A
NG_007941.3:g.7262G>A
NG_008337.2:g.73809C>T
NG_045215.1:g.2795G>A
LRG_829:g.7262G>A
LRG_829t1:c.1100G>A	LRG_829p1:p.Arg367His

... more HGVS ... less HGVS

Protein change

R232H, R337H, R367H

Other names

Canonical SPDI

NC_000006.12:32040565:G:A

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.

Links

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.
CYP21A2		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	23	354
LOC106780800	-	-	-	GRCh38 GRCh38	-	304

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.
not provided	Pathogenic (1)	criteria provided, single submitter	Oct 15, 2022	RCV003482664.2
CYP21A2-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 23, 2024	RCV004754992.1

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 (Oct 15, 2022)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV004229565.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Publications: PubMed (6) PubMed: 32616876‚ 24225272‚ 25087612‚ 26291314‚ 21646284‚ 23359706 Comment: Frequency data for this variant in the general population cannot be distinguished from that of the CYP21P pseudogene, and are therefore uninformative in assessment of … (more) Frequency data for this variant in the general population cannot be distinguished from that of the CYP21P pseudogene, and are therefore uninformative in assessment of variant pathogenicity. This variant has been seen in trans with other recessive pathogenic CYP21A2 variants in multiple individuals with nonclassic CAH or in cases where the type of CAH was not specified. This variant segregates with nonclassic adrenal hyperplasia in one family (PMID: 26291314). (less)
Pathogenic (Jul 23, 2024)	no assertion criteria provided Method: clinical testing	CYP21A2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005348176.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The CYP21A2 c.1100G>A variant is predicted to result in the amino acid substitution p.Arg367His. This variant has been reported to be pathogenic for autosomal recessive … (more) The CYP21A2 c.1100G>A variant is predicted to result in the amino acid substitution p.Arg367His. This variant has been reported to be pathogenic for autosomal recessive congenital adrenal hyperplasia (CAH) (Ghizzoni et al. 2011. PubMed ID: 21646284; Khattab et al. 2015. PubMed ID: 26291314). In Khattab et al. study, this variant has been found in the compound heterozygous state with a severe pathogenic variant in individuals with non-classic (NC) CAH, suggesting this variant is a milder allele associated with NC-CAH likely due to the loss of one of two hydrogen bonds and thus weakening (but not abolishing) the ion pair interaction. This variant is reported in 0.049% of alleles in individuals of African descent in gnomAD. This variant falls within a highly paralogous region. Allele frequency data should be interpreted with caution. This variant is interpreted as pathogenic. (less)

Comment:

Frequency data for this variant in the general population cannot be distinguished from that of the CYP21P pseudogene, and are therefore uninformative in assessment of variant pathogenicity. This variant has been seen in trans with other recessive pathogenic CYP21A2 variants in multiple individuals with nonclassic CAH or in cases where the type of CAH was not specified. This variant segregates with nonclassic adrenal hyperplasia in one family (PMID: 26291314).

Comment:

The CYP21A2 c.1100G>A variant is predicted to result in the amino acid substitution p.Arg367His. This variant has been reported to be pathogenic for autosomal recessive congenital adrenal hyperplasia (CAH) (Ghizzoni et al. 2011. PubMed ID: 21646284; Khattab et al. 2015. PubMed ID: 26291314). In Khattab et al. study, this variant has been found in the compound heterozygous state with a severe pathogenic variant in individuals with non-classic (NC) CAH, suggesting this variant is a milder allele associated with NC-CAH likely due to the loss of one of two hydrogen bonds and thus weakening (but not abolishing) the ion pair interaction. This variant is reported in 0.049% of alleles in individuals of African descent in gnomAD. This variant falls within a highly paralogous region. Allele frequency data should be interpreted with caution. This variant is interpreted 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
EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency.	Baumgartner-Parzer S	European journal of human genetics : EJHG	2020	PMID: 32616876
A rare CYP21A2 mutation in a congenital adrenal hyperplasia kindred displaying genotype-phenotype nonconcordance.	Khattab A	Annals of the New York Academy of Sciences	2016	PMID: 26291314
Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results.	Tabor HK	American journal of human genetics	2014	PMID: 25087612
No evidence of an increase in early infant mortality from congenital adrenal hyperplasia in the absence of screening.	Hird BE	Archives of disease in childhood	2014	PMID: 24225272
Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia.	Haider S	Proceedings of the National Academy of Sciences of the United States of America	2013	PMID: 23359706
Relationship of CYP21A2 genotype and serum 17-hydroxyprogesterone and cortisol levels in a large cohort of Italian children with premature pubarche.	Ghizzoni L	European journal of endocrinology	2011	PMID: 21646284

Text-mined citations for this variant ...

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000500.9(CYP21A2):c.1100G>A (p.Arg367His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...