NM_000197.2(HSD17B3):c.645A>T (p.Glu215Asp) AND Testosterone 17-beta-dehydrogenase deficiency

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: May 23, 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:: RCV003146073.5

Allele description [Variation Report for NM_000197.2(HSD17B3):c.645A>T (p.Glu215Asp)]

NM_000197.2(HSD17B3):c.645A>T (p.Glu215Asp)

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.645A>T (p.Glu215Asp)

HGVS:

NC_000009.12:g.96244356T>A
NG_008157.1:g.62797A>T
NM_000197.2:c.645A>TMANE SELECT
NP_000188.1:p.Glu215Asp
LRG_1296t1:c.645A>T
LRG_1296:g.62797A>T
LRG_1296p1:p.Glu215Asp
NC_000009.11:g.99006638T>A
NM_000197.1:c.645A>T
NR_182427.1:n.3412A>T

Protein change:

E215D

Molecular consequence:

NM_000197.2:c.645A>T - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003829108	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 14, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004190285	Clinical Biochemistry Laboratory, Health Services Laboratory	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 20, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005184994	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 23, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 8550739, 17466011, 10022457 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003829108

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 14, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004190285

Clinical Biochemistry Laboratory, Health Services Laboratory

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 20, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005184994

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(May 23, 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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Molecular genetics and pathophysiology of 17 beta-hydroxysteroid dehydrogenase 3 deficiency.

Andersson S, Geissler WM, Wu L, Davis DL, Grumbach MM, New MI, Schwarz HP, Blethen SL, Mendonca BB, Bloise W, Witchel SF, Cutler GB Jr, Griffin JE, Wilson JD, Russel DW.

J Clin Endocrinol Metab. 1996 Jan;81(1):130-6.

PubMed [citation]

PMID:: 8550739

See all PubMed Citations (4)

Details of each submission

From Revvity Omics, Revvity, SCV003829108.2

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Biochemistry Laboratory, Health Services Laboratory, SCV004190285.1

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

Description

ACMG:PM2 PP3 PP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	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, SCV005184994.1

#	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.645A>T (p.Glu215Asp) results in a 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 4.8e-05 in 251484 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in HSD17B3 causing Testosterone 17-beta-dehydrogenase deficiency, allowing no conclusion about variant significance. c.645A>T has been reported in the literature in multiple individuals affected with Testosterone 17-beta-dehydrogenase deficiency, including homozygotes (Andersson_1996, Mendonca_1999, Lee_2007). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Andersson_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8550739, 17466011, 10022457). ClinVar contains an entry for this variant (Variation ID: 2440772). 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 8, 2024

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