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NM_000500.9(CYP21A2):c.1070G>A (p.Arg357Gln) AND not provided

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 31, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV003089112.2

Allele description

NM_000500.9(CYP21A2):c.1070G>A (p.Arg357Gln)

Genes:
LOC106780800:CYP21A2 recombination region [Gene]
CYP21A2:cytochrome P450 family 21 subfamily A member 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
6p21.33
Genomic location:
Preferred name:
NM_000500.9(CYP21A2):c.1070G>A (p.Arg357Gln)
Other names:
p.Arg357Gln
HGVS:
  • NC_000006.12:g.32040536G>A
  • NG_007941.3:g.7232G>A
  • NG_008337.2:g.73839C>T
  • NG_045215.1:g.2765G>A
  • NM_000500.9:c.1070G>AMANE SELECT
  • NM_001128590.4:c.980G>A
  • NM_001368143.2:c.665G>A
  • NM_001368144.2:c.665G>A
  • NP_000491.4:p.Arg357Gln
  • NP_001122062.3:p.Arg327Gln
  • NP_001355072.1:p.Arg222Gln
  • NP_001355073.1:p.Arg222Gln
  • LRG_829t1:c.1070G>A
  • LRG_829:g.7232G>A
  • LRG_829p1:p.Arg357Gln
  • NC_000006.11:g.32008313G>A
Protein change:
R222Q
Links:
dbSNP: rs574370139
NCBI 1000 Genomes Browser:
rs574370139
Molecular consequence:
  • NM_000500.9:c.1070G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001128590.4:c.980G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368143.2:c.665G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368144.2:c.665G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV003280650Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Dec 31, 2023)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A cluster of missense mutations at Arg356 of human steroid 21-hydroxylase may impair redox partner interaction.

Lajic S, Levo A, Nikoshkov A, Lundberg Y, Partanen J, Wedell A.

Hum Genet. 1997 Jun;99(6):704-9.

PubMed [citation]
PMID:
9187661
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV003280650.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 357 of the CYP21A2 protein (p.Arg357Gln). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individual(s) with classic salt wasting as well as simple virilizing forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 9099839, 9187661, 26804566). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as R356Q. ClinVar contains an entry for this variant (Variation ID: 1675315). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP21A2 protein function. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 9187661). This variant disrupts the p.Arg357 amino acid residue in CYP21A2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9099839, 9187661, 26804566). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 20, 2024