VCV002200699.3 - ClinVar

NM_000197.2(HSD17B3):c.729_735del (p.Ile244fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000197.2(HSD17B3):c.729_735del (p.Ile244fs)

Variation ID: 2200699 Accession: VCV002200699.3

Type and length

Deletion, 7 bp

Location

Cytogenetic: 9q22.32 9: 96240845-96240851 (GRCh38) [ NCBI UCSC ] 9: 99003127-99003133 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2023	Feb 14, 2024	Dec 9, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000197.2:c.729_735del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000188.1:p.Ile244fs	frameshift
NM_000197.1:c.729_735del
NR_182427.1:n.3496_3502delGATAACC
NC_000009.12:g.96240845_96240851del
NC_000009.11:g.99003127_99003133del
NG_008157.1:g.66302_66308del
LRG_1296:g.66302_66308del
LRG_1296t1:c.729_735del	LRG_1296p1:p.Ile244fs

... more HGVS ... less HGVS

Protein change

I244fs

Other names

Canonical SPDI

NC_000009.12:96240844:GGTTATC:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HSD17B3		-	-	GRCh38 GRCh37	9	349
SLC35D2-HSD17B3	-	-	-	GRCh38	-	339

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 9, 2023	RCV002638342.3
Testosterone 17-beta-dehydrogenase deficiency	Pathogenic (1)	criteria provided, single submitter	Nov 20, 2023	RCV003459769.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Testosterone 17-beta-dehydrogenase deficiency Affected status: yes Allele origin: germline	Clinical Biochemistry Laboratory, Health Services Laboratory Accession: SCV004190288.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023	Comment: ACMG:PVS1 PM2 PM3 PP4
Pathogenic (Dec 09, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003520418.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 23796702‚ 25740850‚ 8550739‚ 30668521 Comment: This sequence change creates a premature translational stop signal (p.Ile244Argfs11) in the HSD17B3 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Ile244Argfs11) in the HSD17B3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HSD17B3 are known to be pathogenic (PMID: 23796702, 25740850). This variant is present in population databases (rs777697545, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with 17-beta-hydroxysteroid dehydrogenase type 3 deficiency (PMID: 8550739, 30668521). ClinVar contains an entry for this variant (Variation ID: 2200699). For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This sequence change creates a premature translational stop signal (p.Ile244Argfs*11) in the HSD17B3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HSD17B3 are known to be pathogenic (PMID: 23796702, 25740850). This variant is present in population databases (rs777697545, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with 17-beta-hydroxysteroid dehydrogenase type 3 deficiency (PMID: 8550739, 30668521). ClinVar contains an entry for this variant (Variation ID: 2200699). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD).	Hughes LA	Endocrine connections	2019	PMID: 30668521
Screening for mutations in 17β-hydroxysteroid dehydrogenase and androgen receptor in women presenting with partially virilised 46,XY disorders of sex development.	Phelan N	European journal of endocrinology	2015	PMID: 25740850
A novel nonsense mutation in exon 1 of HSD17B3 gene in an Egyptian 46,XY adult female presenting with primary amenorrhea.	Hassan HA	Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation	2013	PMID: 23796702
Molecular genetics and pathophysiology of 17 beta-hydroxysteroid dehydrogenase 3 deficiency.	Andersson S	The Journal of clinical endocrinology and metabolism	1996	PMID: 8550739

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000197.2(HSD17B3):c.729_735del (p.Ile244fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...