NM_000500.9(CYP21A2):c.1174G>A (p.Ala392Thr) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 14, 2023
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:: RCV003155127.1

Allele description [Variation Report for NM_000500.9(CYP21A2):c.1174G>A (p.Ala392Thr)]

NM_000500.9(CYP21A2):c.1174G>A (p.Ala392Thr)

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.1174G>A (p.Ala392Thr)

Other names:

(p.Ala392Thr)

HGVS:

NC_000006.12:g.32040723G>A
NG_007941.3:g.7419G>A
NG_008337.2:g.73652C>T
NG_045215.1:g.2952G>A
NM_000500.9:c.1174G>AMANE SELECT
NM_001128590.4:c.1084G>A
NM_001368143.2:c.769G>A
NM_001368144.2:c.769G>A
NP_000491.4:p.Ala392Thr
NP_001122062.3:p.Ala362Thr
NP_001355072.1:p.Ala257Thr
NP_001355073.1:p.Ala257Thr
LRG_829t1:c.1174G>A
LRG_829:g.7419G>A
LRG_829p1:p.Ala392Thr
NC_000006.11:g.32008500G>A
NM_000500.5:c.1174G>A
NM_000500.7:c.1174G>A

Protein change:

A257T

Links:

dbSNP: rs202242769

NCBI 1000 Genomes Browser:

rs202242769

Molecular consequence:

NM_000500.9:c.1174G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128590.4:c.1084G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001368143.2:c.769G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001368144.2:c.769G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003844694	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Feb 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17119906, 26300845, 25538881 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003844694

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Feb 14, 2023)

germline

clinical testing

PubMed (3)
[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

Characterization of novel missense mutations in CYP21 causing congenital adrenal hyperplasia.

Robins T, Bellanne-Chantelot C, Barbaro M, Cabrol S, Wedell A, Lajic S.

J Mol Med (Berl). 2007 Mar;85(3):247-55. Epub 2006 Nov 21.

PubMed [citation]

PMID:: 17119906

Whole-Exome Sequencing in the Differential Diagnosis of Primary Adrenal Insufficiency in Children.

Chan LF, Campbell DC, Novoselova TV, Clark AJ, Metherell LA.

Front Endocrinol (Lausanne). 2015;6:113. doi: 10.3389/fendo.2015.00113.

PubMed [citation]

PMID:: 26300845
PMCID:: PMC4525066

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003844694.1

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

Description

Variant summary: CYP21A2 c.1174G>A (p.Ala392Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0092 in 234892 control chromosomes (gnomAD). Due to high homology with the CYP21A1P pseudogene, allele frequency data from the general population is uninformative for the assessment of this variant. c.1174G>A has been reported in the literature in at least one compound heterozygous individual affected with Congenital Adrenal Hyperplasia (e.g. Robins_2007). These data do not allow any conclusion about variant significance. Transient expression in COS-1 cells have demonstrated the variant has 38.9% enzymatic activity for the conversion of 17-OHP and 22.9% activity for progesterone (Robins_2007). Eight ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, three as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly 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: Sep 29, 2024

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