VCV000585755.4 - ClinVar

NM_000500.9(CYP21A2):c.49C>T (p.Arg17Cys)

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.

(3)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000500.9(CYP21A2):c.49C>T (p.Arg17Cys)

Variation ID: 585755 Accession: VCV000585755.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p21.33 6: 32038471 (GRCh38) [ NCBI UCSC ] 6: 32006248 (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 20, 2018	May 12, 2024	Apr 25, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000500.9:c.49C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000491.4:p.Arg17Cys	missense
NM_001128590.4:c.49C>T	NP_001122062.3:p.Arg17Cys	missense
NM_001368143.2:c.-376C>T		5 prime UTR
NM_001368144.2:c.-286C>T		5 prime UTR
NC_000006.12:g.32038471C>T
NC_000006.11:g.32006248C>T
NG_007941.3:g.5167C>T
NG_045215.1:g.700C>T
NG_055451.1:g.5147C>T
LRG_829:g.5167C>T
LRG_829t1:c.49C>T	LRG_829p1:p.Arg17Cys

... more HGVS ... less HGVS

Protein change

R17C

Other names

Canonical SPDI

NC_000006.12:32038470: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 0.00001

Exome Aggregation Consortium (ExAC) 0.00004

Links

dbSNP: rs757608533 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	Uncertain significance (1)	criteria provided, single submitter	Feb 21, 2018	RCV000711381.3
not specified	Uncertain significance (1)	criteria provided, single submitter	Apr 25, 2023	RCV003230580.1
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	Uncertain significance (1)	criteria provided, single submitter	-	RCV004546556.2

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.
Uncertain significance (Feb 21, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000841744.1 First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018	Publications: PubMed (2) PubMed: 27721825‚ 27966633
Uncertain significance (Apr 25, 2023)	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: SCV003929031.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Publications: PubMed (2) PubMed: 32616876‚ 27721825 Comment: Variant summary: CYP21A2 c.49C>T (p.Arg17Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more) Variant summary: CYP21A2 c.49C>T (p.Arg17Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 186390 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.49C>T has been reported in the literature as a heterozygous genotype in at-least one individual with a suspicion of Congenital Adrenal Hyperplasia (example, de Paula_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Adrenal Hyperplasia. At least one publication reports experimental evidence evaluating an impact on protein function (de Paula_2016). The most pronounced variant effect results in >80%-90% of normal CYP21A2 activity in vitro. The following publications have been ascertained in the context of this evaluation (PMID: 32616876, 27721825). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005042669.1 First in ClinVar: May 12, 2024 Last updated: May 12, 2024	Comment: The missense c.49C>T p.Arg17Cys variant in the CYP21A2 gene has been reported in heterozygous carriers and it demonstrated a very mild reduction in enzyme activity, … (more) The missense c.49C>T p.Arg17Cys variant in the CYP21A2 gene has been reported in heterozygous carriers and it demonstrated a very mild reduction in enzyme activity, de Paula Michelatto, Débora et al.,2016. This variant is reported with the allele frequency 0.001% in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Uncertain Significance. The amino acid Arginine at position 17 is changed to a Cystine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg17Cys in CYP21A2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. (less)

Comment:

Variant summary: CYP21A2 c.49C>T (p.Arg17Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 186390 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.49C>T has been reported in the literature as a heterozygous genotype in at-least one individual with a suspicion of Congenital Adrenal Hyperplasia (example, de Paula_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Adrenal Hyperplasia. At least one publication reports experimental evidence evaluating an impact on protein function (de Paula_2016). The most pronounced variant effect results in >80%-90% of normal CYP21A2 activity in vitro. The following publications have been ascertained in the context of this evaluation (PMID: 32616876, 27721825). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

The missense c.49C>T p.Arg17Cys variant in the CYP21A2 gene has been reported in heterozygous carriers and it demonstrated a very mild reduction in enzyme activity, de Paula Michelatto, Débora et al.,2016. This variant is reported with the allele frequency 0.001% in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Uncertain Significance. The amino acid Arginine at position 17 is changed to a Cystine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg17Cys in CYP21A2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

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
Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations.	Bruque CD	Scientific reports	2016	PMID: 27966633
Functional and Structural Consequences of Nine CYP21A2 Mutations Ranging from Very Mild to Severe Effects.	de Paula Michelatto D	International journal of endocrinology	2016	PMID: 27721825

Text-mined citations for rs757608533 ...

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 Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_000500.9(CYP21A2):c.49C>T (p.Arg17Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs757608533 ...