NM_000197.2(HSD17B3):c.645A>T (p.Glu215Asp) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 22, 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:: RCV003561189.2

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004277996	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10599740, 17466011, 27163392, 27899157, 30668521, 28492532
SCV005326069	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 5, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004277996

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 22, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV005326069

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Dec 5, 2023)

germline

clinical testing

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

17Beta-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations.

Boehmer AL, Brinkmann AO, Sandkuijl LA, Halley DJ, Niermeijer MF, Andersson S, de Jong FH, Kayserili H, de Vroede MA, Otten BJ, Rouwé CW, Mendonça BB, Rodrigues C, Bode HH, de Ruiter PE, Delemarre-van de Waal HA, Drop SL.

J Clin Endocrinol Metab. 1999 Dec;84(12):4713-21.

PubMed [citation]

PMID:: 10599740

Phenotypic variability in 17beta-hydroxysteroid dehydrogenase-3 deficiency and diagnostic pitfalls.

Lee YS, Kirk JM, Stanhope RG, Johnston DI, Harland S, Auchus RJ, Andersson S, Hughes IA.

Clin Endocrinol (Oxf). 2007 Jul;67(1):20-8. Epub 2007 Apr 27.

PubMed [citation]

PMID:: 17466011

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004277996.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 215 of the HSD17B3 protein (p.Glu215Asp). This variant is present in population databases (rs115063639, gnomAD 0.009%). This missense change has been observed in individual(s) with 17-beta-hydroxysteroid dehydrogenase type 3 deficiency (PMID: 10599740, 17466011, 27163392, 27899157, 30668521). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2440772). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HSD17B3 protein function with a positive predictive value of 80%. For these reasons, this variant has been 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

From GeneDx, SCV005326069.1

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

Description

Published functional studies demonstrate a damaging effect with a near complete loss of enzyme activity (PMID: 8550739); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10599740, 25298885, 8550739, 34946839, 17466011, 27899157, 36077423, 35134971, 35065919, 33984517, 35432193, 36675662, 30668521, 27163392)

#	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

Last Updated: Oct 8, 2024

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