NM_000102.4(CYP17A1):c.1039C>T (p.Arg347Cys) AND Deficiency of steroid 17-alpha-monooxygenase

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 7, 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:: RCV002221463.4

Allele description [Variation Report for NM_000102.4(CYP17A1):c.1039C>T (p.Arg347Cys)]

NM_000102.4(CYP17A1):c.1039C>T (p.Arg347Cys)

Gene:

CYP17A1:cytochrome P450 family 17 subfamily A member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q24.32

Genomic location:

Preferred name:

NM_000102.4(CYP17A1):c.1039C>T (p.Arg347Cys)

HGVS:

NC_000010.11:g.102832611G>A
NG_007955.1:g.9923C>T
NM_000102.4:c.1039C>TMANE SELECT
NP_000093.1:p.Arg347Cys
NC_000010.10:g.104592368G>A
NM_000102.3:c.1039C>T
P05093:p.Arg347Cys

Protein change:

R347C; ARG347CYS

Links:

UniProtKB: P05093#VAR_022752; OMIM: 609300.0021; dbSNP: rs104894149

NCBI 1000 Genomes Browser:

rs104894149

Molecular consequence:

NM_000102.4:c.1039C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Deficiency of steroid 17-alpha-monooxygenase
Synonyms:: ADRENAL HYPERPLASIA V; 17-alpha-hydroxylase deficiency; Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008730; MedGen: C0268285; OMIM: 202110

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002498764	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 23, 2021)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12466376, 9326943, 25741868
SCV004215425	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 7, 2024)	unknown	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

SCV002498764

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 23, 2021)

unknown

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004215425

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 7, 2024)

unknown

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	yes	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

Differential inhibition of 17alpha-hydroxylase and 17,20-lyase activities by three novel missense CYP17 mutations identified in patients with P450c17 deficiency.

Van Den Akker EL, Koper JW, Boehmer AL, Themmen AP, Verhoef-Post M, Timmerman MA, Otten BJ, Drop SL, De Jong FH.

J Clin Endocrinol Metab. 2002 Dec;87(12):5714-21.

PubMed [citation]

PMID:: 12466376

The genetic and functional basis of isolated 17,20-lyase deficiency.

Geller DH, Auchus RJ, Mendonça BB, Miller WL.

Nat Genet. 1997 Oct;17(2):201-5.

PubMed [citation]

PMID:: 9326943

See all PubMed Citations (3)

Details of each submission

From Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital, SCV002498764.1

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

Description

The CYP17A1 p.Arg347Cys variant is in exon 6 of 8 and falls within the redox partner interaction domain of the protein. It is rare in large population cohorts (1 of 251,414 alleles, gnomAD v2.1.1). In vitro assays show that the p.Arg347Cys alteration leads to partial loss of 17-alpha-hydroxylase activity with near complete loss of 17,20-lyase activity. Two individuals with 46,XY karyotypes and partial 17α-hydroxylase deficiency and complete 17,20-lyase deficiency were found to carry the p.Arg347Cys along with a second pathogenic variant (See patients 3 and 4 from PMID: 12466376). A different missense variant at this position (p.Arg347His) has been observed in the homozygous state in multiple affected individuals (PMID: 12466376, PMID: 9326943).

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

From Baylor Genetics, SCV004215425.2

#	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	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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