NM_000500.9(CYP21A2):c.724C>G (p.Leu242Val) AND Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 13, 2024
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:: RCV000984607.3

Allele description [Variation Report for NM_000500.9(CYP21A2):c.724C>G (p.Leu242Val)]

NM_000500.9(CYP21A2):c.724C>G (p.Leu242Val)

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.724C>G (p.Leu242Val)

HGVS:

NC_000006.12:g.32039821C>G
NG_007941.3:g.6517C>G
NG_008337.2:g.74554G>C
NG_045215.1:g.2050C>G
NM_000500.9:c.724C>GMANE SELECT
NM_001128590.4:c.634C>G
NM_001368143.2:c.319C>G
NM_001368144.2:c.319C>G
NP_000491.4:p.Leu242Val
NP_001122062.3:p.Leu212Val
NP_001355072.1:p.Leu107Val
NP_001355073.1:p.Leu107Val
LRG_829t1:c.724C>G
LRG_829:g.6517C>G
LRG_829p1:p.Leu242Val
NC_000006.11:g.32007598C>G
NM_000500.7:c.724C>G

Protein change:

L107V

Links:

dbSNP: rs1582306855

NCBI 1000 Genomes Browser:

rs1582306855

Molecular consequence:

NM_000500.9:c.724C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001128590.4:c.634C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001368143.2:c.319C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001368144.2:c.319C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Synonyms:: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency; CYP21 deficiency; 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia
Identifiers:: MONDO: MONDO:0008728; MedGen: C2936858; Orphanet: 90794; OMIM: 201910

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001132665	Institute of Human Genetics, Medical University Innsbruck	no assertion criteria provided	Uncertain significance (May 24, 2019)	unknown	clinical testing
SCV005061363	Gemeinschaftspraxis fuer Humangenetik Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 13, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001132665

Institute of Human Genetics, Medical University Innsbruck

no assertion criteria provided

Uncertain significance
(May 24, 2019)

unknown

clinical testing

SCV005061363

Gemeinschaftspraxis fuer Humangenetik Dresden

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 13, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Institute of Human Genetics, Medical University Innsbruck, SCV001132665.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Gemeinschaftspraxis fuer Humangenetik Dresden, SCV005061363.1

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

Description

This gene alteration is not listed in HGMD® (Professional 2023.4). However, the alteration c.725T>C, p.(Leu242Pro) is already listed at the same amino acid position as pathogenic for the phenotype of “adrenal hyperplasia” (CM191848). Furthermore, the variant is classified by one author in ClinVar as a “variant of unclear significance”, is not listed in the LOVD (https://databases.lovd.nl/shared/genes/CYP21A2) and has an allele frequency of 0.0002% in gnomAD (European, non-Finnish). In summary, the variant should currently be classified as uncertain significance.

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

Last Updated: Jun 29, 2024

ClinVar

Relating variation to medicine