NM_000500.9(CYP21A2):c.1024C>T (p.Arg342Trp) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 6, 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:: RCV001919442.6

Allele description [Variation Report for NM_000500.9(CYP21A2):c.1024C>T (p.Arg342Trp)]

NM_000500.9(CYP21A2):c.1024C>T (p.Arg342Trp)

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.1024C>T (p.Arg342Trp)

HGVS:

NC_000006.12:g.32040490C>T
NG_007941.3:g.7186C>T
NG_008337.2:g.73885G>A
NG_045215.1:g.2719C>T
NM_000500.7:c.1024C>T
NM_000500.9:c.1024C>TMANE SELECT
NM_001128590.4:c.934C>T
NM_001368143.2:c.619C>T
NM_001368144.2:c.619C>T
NP_000491.4:p.Arg342Trp
NP_001122062.3:p.Arg312Trp
NP_001355072.1:p.Arg207Trp
NP_001355073.1:p.Arg207Trp
LRG_829t1:c.1024C>T
LRG_829:g.7186C>T
LRG_829p1:p.Arg342Trp
NC_000006.11:g.32008267C>T

Protein change:

R207W

Links:

dbSNP: rs72552755

NCBI 1000 Genomes Browser:

rs72552755

Molecular consequence:

NM_000500.9:c.1024C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128590.4:c.934C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001368143.2:c.619C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001368144.2:c.619C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002192437	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 6, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29328376, 24953648, 28492532
SCV004221762	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	pathogenic (Aug 4, 2023)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 36167262, 28392195, 24953648, 23359706, 29328376, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002192437

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 6, 2023)

germline

clinical testing

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

SCV004221762

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

pathogenic
(Aug 4, 2023)

unknown

clinical testing

PubMed (6)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Nonclassic Adrenal Hyperplasia (NCAH) due to 21-hydroxylase deficiency: A cohort of 78 patients.

Wan Z, Wang W, Zheng S, Han R, Xie X, Zhao Y, Wang W, Sun S, Ye L.

J Steroid Biochem Mol Biol. 2023 Jan;225:106192. doi: 10.1016/j.jsbmb.2022.106192. Epub 2022 Sep 24.

PubMed [citation]

PMID:: 36167262

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002192437.3

#	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 arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 342 of the CYP21A2 protein (p.Arg342Trp). 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 non-classic and simple virilizing congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 24953648, 29328376). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as R341W. ClinVar contains an entry for this variant (Variation ID: 1422248). 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 CYP21A2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 24953648). For these reasons, this variant has been classified as Pathogenic.

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004221762.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The CYP21A2 c.1024C>T (p.Arg342Trp) variant (also known as R342W or R341W) has been reported in the published literature in individuals affected with nonclassical CAH (PMIDs: 24953648 (2015), 29328376 (2018), 36167262 (2023)). This variant has shown to result in reduced enzymatic activity (PMID: 24953648 (2015)). Based on the available information, this variant is classified as pathogenic.

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

Last Updated: Oct 13, 2024

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