VCV002138722.3 - ClinVar

NM_000194.3(HPRT1):c.289_290del (p.Val97fs)

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_000194.3(HPRT1):c.289_290del (p.Val97fs)

Variation ID: 2138722 Accession: VCV002138722.3

Type and length

Deletion, 2 bp

Location

Cytogenetic: Xq26.2 X: 134475334-134475335 (GRCh38) [ NCBI UCSC ] X: 133609364-133609365 (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 28, 2024	Sep 22, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000194.3:c.289_290del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000185.1:p.Val97fs	frameshift
NM_000194.3:c.289_290delGT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000023.11:g.134475335_134475336del
NC_000023.10:g.133609365_133609366del
NG_012329.2:g.20191_20192del

... more HGVS ... less HGVS

Protein change

V97fs

Other names

Canonical SPDI

NC_000023.11:134475333:TGT:T

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.
HPRT1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	233	430

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.
Lesch-Nyhan syndrome Partial hypoxanthine-guanine phosphoribosyltransferase deficiency	Pathogenic (1)	criteria provided, single submitter	Sep 22, 2022	RCV003050653.3
Lesch-Nyhan syndrome	Pathogenic (1)	criteria provided, single submitter	-	RCV003318326.1

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lesch-Nyhan syndrome Affected status: yes Allele origin: biparental	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV004021935.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Pathogenic (Sep 22, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Lesch-Nyhan syndrome Partial hypoxanthine-guanine phosphoribosyltransferase deficiency Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003445781.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 2928313‚ 9288634‚ 15571220‚ 17027311‚ 22157001 Comment: For these reasons, this variant has been classified as Pathogenic. This variant is also known as 289delGT and 2bp deletion. This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. This variant is also known as 289delGT and 2bp deletion. This premature translational stop signal has been observed in individual(s) with HPRT-related conditions (PMID: 2928313, 9288634). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val97Argfs*10) in the HPRT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPRT1 are known to be pathogenic (PMID: 15571220, 17027311, 22157001). (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant is also known as 289delGT and 2bp deletion. This premature translational stop signal has been observed in individual(s) with HPRT-related conditions (PMID: 2928313, 9288634). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val97Argfs*10) in the HPRT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPRT1 are known to be pathogenic (PMID: 15571220, 17027311, 22157001).

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
Genotype-phenotype correlations in Lesch-Nyhan disease: moving beyond the gene.	Fu R	The Journal of biological chemistry	2012	PMID: 22157001
Molecular analysis of HPRT deficiencies: an update of the spectrum of Asian mutations with novel mutations.	Yamada Y	Molecular genetics and metabolism	2007	PMID: 17027311
The spectrum of mutations causing HPRT deficiency: an update.	Jinnah HA	Nucleosides, nucleotides & nucleic acids	2004	PMID: 15571220
Molecular analysis of hypoxanthine guanine phosphoribosyltransferase (HPRT) gene in five Korean families with Lesch-Nyhan syndrome.	Kim KJ	Journal of Korean medical science	1997	PMID: 9288634
Identification of mutations leading to the Lesch-Nyhan syndrome by automated direct DNA sequencing of in vitro amplified cDNA.	Gibbs RA	Proceedings of the National Academy of Sciences of the United States of America	1989	PMID: 2928313

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000194.3(HPRT1):c.289_290del (p.Val97fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...