NM_000197.2(HSD17B3):c.238C>T (p.Arg80Trp) AND Testosterone 17-beta-dehydrogenase deficiency

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Aug 19, 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:: RCV000005153.9

Allele description [Variation Report for NM_000197.2(HSD17B3):c.238C>T (p.Arg80Trp)]

NM_000197.2(HSD17B3):c.238C>T (p.Arg80Trp)

Genes:

SLC35D2-HSD17B3:SLC35D2-HSD17B3 readthrough [Gene]
HSD17B3:hydroxysteroid 17-beta dehydrogenase 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q22.32

Genomic location:

Preferred name:

NM_000197.2(HSD17B3):c.238C>T (p.Arg80Trp)

HGVS:

NC_000009.12:g.96254907G>A
NG_008157.1:g.52246C>T
NM_000197.2:c.238C>TMANE SELECT
NP_000188.1:p.Arg80Trp
LRG_1296t1:c.238C>T
LRG_1296:g.52246C>T
LRG_1296p1:p.Arg80Trp
NC_000009.11:g.99017189G>A
NM_000197.1:c.238C>T
P37058:p.Arg80Trp

Protein change:

R80W; ARG80TRP

Links:

UniProtKB: P37058#VAR_006954; OMIM: 605573.0007; dbSNP: rs119481077

NCBI 1000 Genomes Browser:

rs119481077

Molecular consequence:

NM_000197.2:c.238C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Testosterone 17-beta-dehydrogenase deficiency
Synonyms:: 17-beta hydroxysteroid dehydrogenase 3 deficiency; 17 alpha ketosteroid reductase deficiency of testis; 17 alpha KSR deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009916; MedGen: C0268296; Orphanet: 752; OMIM: 264300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000025330	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 1998)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000481365	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 27, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9758445, 21214500, 24025597, 19498320, 22212252 Citation Link,
SCV002572699	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005380891	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 19, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9758445, 22212252 Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	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	literature only

Citations

PubMed

Isolated mild clitoral hypertrophy may reveal 46,XY disorders of sex development in infancy due to 17βHSD-3 defect confirmed by molecular analysis.

George MM, Sinha S, Mamkin I, Philibert P, New MI, Wilson RC, Sultan C, Ten S, Bhangoo A.

Gynecol Endocrinol. 2011 Nov;27(11):890-4. doi: 10.3109/09513590.2010.544134. Epub 2011 Jan 10.

PubMed [citation]

PMID:: 21214500

Complexities of gender assignment in 17β-hydroxysteroid dehydrogenase type 3 deficiency: is there a role for early orchiectomy?

Chuang J, Vallerie A, Breech L, Saal HM, Alam S, Crawford P, Rutter MM.

Int J Pediatr Endocrinol. 2013 Sep 12;2013(1):15. doi: 10.1186/1687-9856-2013-15.

PubMed [citation]

PMID:: 24025597
PMCID:: PMC3847283

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000025330.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Bilbao et al. (1998) described a 46,XY infant in whom the diagnosis of male pseudohermaphroditism (264300) was made at birth. The child also had a giant omphalocele and tetralogy of Fallot, and died of postsurgical complications at the age of 4.5 months. Autopsy confirmed the absence of the uterus or other mullerian structures, and showed well-developed wolffian structures, including epididymis and vas deferens. Microscopic examination of the testes showed normal testicular histology. Messenger RNA extracted from the patient's testis was used to synthesize HSD17B3 cDNA. Sequencing revealed a homozygous missense mutation, arg80 to trp, in exon 3 of the HSD17B3 gene. The mutation was present in heterozygous state in each of the parents. The arg80-to-trp mutation was due to a change of CGG to TGG; a different missense mutation in the same position, R80Q (605573.0003), due to a CGG to CAG change, had been reported in several patients.

#	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

From Illumina Laboratory Services, Illumina, SCV000481365.3

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

Description

The HSD17B3 c.238C>T (p.Arg80Trp) variant has been reported in five studies and is found in a total of eight individuals with 17-beta-hydroxysteroid dehydrogenase III deficiency, including six who carried the variant in a homozygous state and two who carried the variant in a compound heterozygous state (Bilbao et al. 1998; Bertelloni et al. 2009; Omrani et al. 2011; George et al. 2011; Chuang et al. 2013). The variant has also been reported in a heterozygous state in at least eight unaffected family members and shown to segregate with disease in an autosomal recessive fashion (Bilbao et al. 1998; Omrani et al. 2011; George et al. 2011). The p.Arg80Trp variant was absent from 42 controls and is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg80Trp variant is classified as pathogenic for 17-beta-hydroxysteroid dehydrogenase III deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 3billion, SCV002572699.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.92). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000004877 / PMID: 24025597 ) and a different missense change at the same codon (p.Arg80Gln; ClinVar ID: VCV000004874 ) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005380891.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: HSD17B3 c.238C>T (p.Arg80Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251118 control chromosomes (gnomAD). c.238C>T has been reported in the literature in multiple individuals affected with Testosterone 17-beta-dehydrogenase deficiency (e.g. Bilbao_1998, Omrani_2011). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9758445, 22212252). ClinVar contains an entry for this variant (Variation ID: 4877). Based on the evidence outlined above, the variant was 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 26, 2024

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