NM_000500.9(CYP21A2):c.1273G>A (p.Gly425Ser) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 4, 2024
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:: RCV000991861.9

Allele description [Variation Report for NM_000500.9(CYP21A2):c.1273G>A (p.Gly425Ser)]

NM_000500.9(CYP21A2):c.1273G>A (p.Gly425Ser)

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.1273G>A (p.Gly425Ser)

Other names:

G424S

HGVS:

NC_000006.12:g.32040919G>A
NG_007941.3:g.7615G>A
NG_008337.2:g.73456C>T
NG_045215.1:g.3148G>A
NM_000500.9:c.1273G>AMANE SELECT
NM_001128590.4:c.1183G>A
NM_001368143.2:c.868G>A
NM_001368144.2:c.868G>A
NP_000491.4:p.Gly425Ser
NP_001122062.3:p.Gly395Ser
NP_001355072.1:p.Gly290Ser
NP_001355073.1:p.Gly290Ser
LRG_829t1:c.1273G>A
LRG_829:g.7615G>A
LRG_829p1:p.Gly425Ser
NC_000006.11:g.32008696G>A
NC_000006.11:g.32008696G>A
NM_000500.7:c.1273G>A

Protein change:

G290S; GLY424SER

Links:

OMIM: 613815.0025; dbSNP: rs72552758

NCBI 1000 Genomes Browser:

rs72552758

Molecular consequence:

NM_000500.9:c.1273G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128590.4:c.1183G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001368143.2:c.868G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001368144.2:c.868G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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LACBIDRAFT_188129 [Laccaria bicolor S238N-H82]
LACBIDRAFT_188129 [Laccaria bicolor S238N-H82]
Gene ID:6070264

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001143689	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Sep 25, 2018)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 10443693, 27185867, 26172259, 16427797, 20661889, 28819757, 30048636, 20080860, 23322511, 16793961, 15670187, 16788163, 21534945, 17803691, 24622265, 21609351, 26467025
SCV002174940	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10443693, 16427797, 27185867, 20080860, 28492532
SCV004221764	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Sep 25, 2018)	unknown	clinical testing	PubMed (18) [See all records that cite these PMIDs] 10443693, 27185867, 26172259, 16427797, 20661889, 28819757, 30048636, 20080860, 23322511, 16793961, 15670187, 16788163, 21534945, 17803691, 24622265, 21609351, 33864926, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001143689

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Sep 25, 2018)

germline

clinical testing

PubMed (17)
[See all records that cite these PMIDs]

SCV002174940

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 4, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004221764

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Sep 25, 2018)

unknown

clinical testing

PubMed (18)
[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

A novel missense mutation, GLY424SER, in Brazilian patients with 21-hydroxylase deficiency.

Billerbeck AE, Bachega TA, Frazatto ET, Nishi MY, Goldberg AC, Marin ML, Madureira G, Monte O, Arnhold IJ, Mendonca BB.

J Clin Endocrinol Metab. 1999 Aug;84(8):2870-2.

PubMed [citation]

PMID:: 10443693

See all PubMed Citations (19)

Details of each submission

From Athena Diagnostics, SCV001143689.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease. However, available data lack unaffected family members.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002174940.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 425 of the CYP21A2 protein (p.Gly425Ser). 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, simple virilizing, and/or non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 10443693, 16427797, 20080860, 27185867). This variant is also known as G424S. ClinVar contains an entry for this variant (Variation ID: 804725). 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: 20080860). 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, SCV004221764.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

The frequency of this variant in the general population, 0.000018 (3/163636 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in multiple patients affected with classical simple virilizing (SV) CAH, as well as in patients with a non-classic (NC) CAH phenotype (PMID: 10443693 (1999), 16427797 (2006), 17803691 (2008), 20661889 (2010), 24622265 (2013), 27185867 (2016), 33864926 (2021)). Functional studies have shown that this variant had very little enzymatic activity (PMID: 20080860 (2010)). 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: Sep 29, 2024

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