NM_000500.9(CYP21A2):c.844G>T (p.Val282Leu) AND Inborn genetic diseases

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 20, 2022
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:: RCV000210728.4

Allele description [Variation Report for NM_000500.9(CYP21A2):c.844G>T (p.Val282Leu)]

NM_000500.9(CYP21A2):c.844G>T (p.Val282Leu)

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.844G>T (p.Val282Leu)

Other names:

V281L; CYP21A2*15

HGVS:

NC_000006.12:g.32040110G>T
NG_007941.3:g.6806G>T
NG_008337.2:g.74265C>A
NG_045215.1:g.2339G>T
NM_000500.9:c.844G>TMANE SELECT
NM_001128590.4:c.754G>T
NM_001368143.2:c.439G>T
NM_001368144.2:c.439G>T
NP_000491.4:p.Val282Leu
NP_001122062.3:p.Val252Leu
NP_001355072.1:p.Val147Leu
NP_001355073.1:p.Val147Leu
LRG_829t1:c.844G>T
LRG_829:g.6806G>T
LRG_829p1:p.Val282Leu
NC_000006.11:g.32007887G>T
NM_000500.5:c.844G>T
NM_000500.7:c.844G>T
p.Val282Leu

Protein change:

V147L; VAL281LEU

Links:

OMIM: 613815.0002; OMIM: 613815.0033; dbSNP: rs6471

NCBI 1000 Genomes Browser:

rs6471

Molecular consequence:

NM_000500.9:c.844G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128590.4:c.754G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001368143.2:c.439G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001368144.2:c.439G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000263011	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 20, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20661889, 23359698, 23359706, 25041270, 28161392 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000263011

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 20, 2022)

germline

clinical testing

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

Citation Link

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

Citations

PubMed

Carrier detection and prenatal diagnosis of congenital adrenal hyperplasia must identify 'apparently mild' CYP21A2 alleles which associate neonatal salt-wasting disease.

Ezquieta B, Santomé L, Barrio R, Barrionuevo JL, López-Siguero JP, Oliver A, Ramírez J, Rodríguez I, Muñoz-Pacheco R.

Prenat Diagn. 2010 Aug;30(8):758-63. doi: 10.1002/pd.2537.

PubMed [citation]

PMID:: 20661889

Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency.

New MI, Abraham M, Gonzalez B, Dumic M, Razzaghy-Azar M, Chitayat D, Sun L, Zaidi M, Wilson RC, Yuen T.

Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):2611-6. doi: 10.1073/pnas.1300057110. Epub 2013 Jan 28.

PubMed [citation]

PMID:: 23359698
PMCID:: PMC3574953

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000263011.7

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

Description

The c.844G>T (p.V282L) alteration is located in coding exon 7 of the CYP21A2 gene. This alteration results from a G to T substitution at nucleotide position 844, causing the valine (V) at amino acid position 282 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.55% (1508/273420) total alleles studied. The highest observed frequency was 2.45% (223/9116) of Ashkenazi Jewish alleles. Data at this locus may not be reliable due to high homology with a pseudogene. This alteration, previously known as V281L, was detected in 94 patients with mild forms of 21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH) and compound heterozygous with a severe mutation (Ezquieta, 2010). This alteration is typically associated with non-classic 21-OHD CAH when homozygous or compound heterozygous, even with a severe pathogenic variant (New, 2013; Livadas, 2015; Rodriguez 2017). This amino acid position is not well conserved in available vertebrate species. Functional analysis demonstrated that the p.V282L alteration reduces 21-hydroxylase activity by about 50% due to an increase in chain length resulting in relatively modest steric clashes in the I-helix of the protein (Haider, 2013; New, 2013). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is 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: Oct 13, 2024

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