NM_000500.9(CYP21A2):c.518T>A (p.Ile173Asn) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Aug 22, 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:: RCV000711382.18

Allele description

NM_000500.9(CYP21A2):c.518T>A (p.Ile173Asn)

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.518T>A (p.Ile173Asn)

Other names:

I172N; rs6475

HGVS:

NC_000006.12:g.32039426T>A
NG_007941.3:g.6122T>A
NG_008337.2:g.74949A>T
NG_045215.1:g.1655T>A
NM_000500.9:c.518T>AMANE SELECT
NM_001128590.4:c.428T>A
NM_001368143.2:c.113T>A
NM_001368144.2:c.113T>A
NP_000491.4:p.Ile173Asn
NP_001122062.3:p.Ile143Asn
NP_001355072.1:p.Ile38Asn
NP_001355073.1:p.Ile38Asn
LRG_829t1:c.518T>A
LRG_829:g.6122T>A
LRG_829p1:p.Ile173Asn
NC_000006.11:g.32007203T>A
NG_007941.2:g.6119T>A
NM_000500.2:c.518T>A
NM_000500.5:c.518T>A
NM_000500.7:c.518T>A

Protein change:

I143N; ILE172ASN

Links:

OMIM: 613815.0001; dbSNP: rs6475

NCBI 1000 Genomes Browser:

rs6475

Molecular consequence:

NM_000500.9:c.518T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128590.4:c.428T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001368143.2:c.113T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001368144.2:c.113T>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000841745	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Aug 22, 2023)	unknown	clinical testing	PubMed (16) [See all records that cite these PMIDs] 16075929, 17042033, 24671123, 14513879, 25501839, 24667412, 2249999, 3257825, 31586465, 23359698, 23359706, 22270556, 21098686, 19750867, 8112748, 26467025
SCV000854779	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Pathogenic (Jul 20, 2018)	germline	clinical testing	Citation Link,
SCV001449827	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 9, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001469964	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Aug 22, 2023)	unknown	clinical testing	PubMed (16) [See all records that cite these PMIDs] 16075929, 17042033, 24671123, 14513879, 25501839, 24667412, 2249999, 3257825, 31586465, 23359698, 23359706, 22270556, 21098686, 19750867, 8112748, 26467025
SCV002018112	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 20, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003252584	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 31, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 3257825, 8698338, 23359698, 26804566, 2249999, 30968594, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	43	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	3	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

An 88-year-old woman diagnosed with adrenal tumor and congenital adrenal hyperplasia: connection or coincidence?

Falhammar H, Thorén M.

J Endocrinol Invest. 2005 May;28(5):449-53.

PubMed [citation]

PMID:: 16075929

Gene duplications in 21-hydroxylase deficiency: the importance of accurate molecular diagnosis in carrier detection and prenatal diagnosis.

Ezquieta B, Beneyto M, Muñoz-Pacheco R, Barrio R, Oyarzabal M, Lechuga JL, Luzuriaga C, Hermoso F, Quinteiro S, Martinez S.

Prenat Diagn. 2006 Dec;26(12):1172-8.

PubMed [citation]

PMID:: 17042033

See all PubMed Citations (21)

Details of each submission

From Athena Diagnostics, SCV000841745.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

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 is also referred to as p.Ile172Asn in published literature. In multiple individuals, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2, suggesting this variant is also pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments demonstrate this variant results in dramatically reduced enzymatic activity (PMID: 2249999, 24667412, 24671123).

#	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

From Eurofins Ntd Llc (ga), SCV000854779.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

#	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		3	not provided	not provided	not provided

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001449827.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	43	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		43	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001469964.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

The CYP21A2 c.518T>A (p.Ile173Asn) variant (also known as I173N or I172N) has been reported in the published literature in individuals affected with the classic salt-wasting, simple virilizing, and non-classic forms of CAH (PMIDs: 3257825 (1988), 17042033 (2006), 21098686 (2011), 23359698 (2013), 31586465 (2020)). In addition, experimental studies indicate this variant is damaging to protein function (PMIDs: 2249999 (1990), 24667412 (2014), 24671123 (2014)). The frequency of this variant in the general population, 0.0016 (41/25010 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. 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

From Revvity Omics, Revvity, SCV002018112.3

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

#	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 Invitae, SCV003252584.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 173 of the CYP21A2 protein (p.Ile173Asn). 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 non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 3257825, 8698338, 23359698, 26804566, 30968594). 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 I172N. ClinVar contains an entry for this variant (Variation ID: 12150). 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. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 2249999, 30968594). 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

Last Updated: Aug 4, 2024

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