NM_000197.2(HSD17B3):c.641A>G (p.Glu214Gly) AND Testosterone 17-beta-dehydrogenase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Apr 5, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001167098.5

Allele description [Variation Report for NM_000197.2(HSD17B3):c.641A>G (p.Glu214Gly)]

NM_000197.2(HSD17B3):c.641A>G (p.Glu214Gly)

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.641A>G (p.Glu214Gly)

HGVS:

NC_000009.12:g.96244360T>C
NG_008157.1:g.62793A>G
NM_000197.2:c.641A>GMANE SELECT
NP_000188.1:p.Glu214Gly
LRG_1296t1:c.641A>G
LRG_1296:g.62793A>G
LRG_1296p1:p.Glu214Gly
NC_000009.11:g.99006642T>C
NC_000009.11:g.99006642T>C
NM_000197.1:c.641A>G

Protein change:

E214G

Links:

dbSNP: rs370264627

NCBI 1000 Genomes Browser:

rs370264627

Molecular consequence:

NM_000197.2:c.641A>G - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001329548	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 12, 2018)	germline	clinical testing	Citation Link,
SCV005077347	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 5, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 36110220, 33468338, 33984517 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001329548

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 12, 2018)

germline

clinical testing

Citation Link,

SCV005077347

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 5, 2024)

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

Novel Genomic Variants, Atypical Phenotypes and Evidence of a Digenic/Oligogenic Contribution to Disorders/Differences of Sex Development in a Large North African Cohort.

Zidoune H, Ladjouze A, Chellat-Rezgoune D, Boukri A, Dib SA, Nouri N, Tebibel M, Sifi K, Abadi N, Satta D, Benelmadani Y, Bignon-Topalovic J, El-Zaiat-Munsch M, Bashamboo A, McElreavey K.

Front Genet. 2022;13:900574. doi: 10.3389/fgene.2022.900574.

PubMed [citation]

PMID:: 36110220
PMCID:: PMC9468775

How Far Should We Explore Hypospadias? Next-generation Sequencing Applied to a Large Cohort of Hypospadiac Patients.

Ea V, Bergougnoux A, Philibert P, Servant-Fauconnet N, Faure A, Breaud J, Gaspari L, Sultan C, Paris F, Kalfa N.

Eur Urol. 2021 Apr;79(4):507-515. doi: 10.1016/j.eururo.2020.12.036. Epub 2021 Jan 16.

PubMed [citation]

PMID:: 33468338

See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001329548.1

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005077347.1

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

Description

Variant summary: HSD17B3 c.641A>G (p.Glu214Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251476 control chromosomes. c.641A>G has been reported in the literature in individuals affected with clinical features of Testosterone 17-beta-dehydrogenase deficiency (e.g., Luna_2021, Zidoune_2022, Ea_2021). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. Transfected HEK-293 cells with the variant demonstrated significantly reduced conversion of androstenedione to testosterone compared to WT. The following publications have been ascertained in the context of this evaluation (PMID: 33468338, 33984517, 36110220). ClinVar contains an entry for this variant (Variation ID: 913468). Based on the evidence outlined above, the variant was classified as likely 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

ClinVar

Relating variation to medicine