VCV000000084.20 - ClinVar

NM_021828.5(HPSE2):c.1465_1466del (p.Asn489fs)

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.

(8)

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/Likely 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_021828.5(HPSE2):c.1465_1466del (p.Asn489fs)

Variation ID: 84 Accession: VCV000000084.20

Type and length

Deletion, 2 bp

Location

Cytogenetic: 10q24.2 10: 98490051-98490052 (GRCh38) [ NCBI UCSC ] 10: 100249808-100249809 (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	Oct 2, 2013	Feb 14, 2024	Oct 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_021828.5:c.1465_1466del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_068600.4:p.Asn489fs	frameshift
NM_001166244.1:c.1291_1292del	NP_001159716.1:p.Asn431fs	frameshift
NM_001166245.1:c.1129_1130del	NP_001159717.1:p.Asn377fs	frameshift
NM_001166246.1:c.1465_1466del	NP_001159718.1:p.Asn489fs	frameshift
NM_021828.4:c.1465_1466delAA
NC_000010.11:g.98490051_98490052del
NC_000010.10:g.100249808_100249809del
NG_023416.1:g.750824_750825del

... more HGVS ... less HGVS

Protein change

N377fs, N431fs, N489fs

Other names

Canonical SPDI

NC_000010.11:98490050:TT:

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.

Exome Aggregation Consortium (ExAC) 0.00016

The Genome Aggregation Database (gnomAD), exomes 0.00016

The Genome Aggregation Database (gnomAD) 0.00019

Trans-Omics for Precision Medicine (TOPMed) 0.00021

1000 Genomes Project 30x 0.00031

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00032

Links

ClinGen: CA339791 OMIM: 613469.0002 dbSNP: rs397515338 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.
HPSE2		-	-	GRCh38 GRCh37	171	193

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.
Urofacial syndrome type 1	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Dec 13, 2022	RCV000000104.22
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 18, 2023	RCV001241819.5

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 (May 22, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Urofacial syndrome type 1 Affected status: unknown Allele origin: maternal	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000782663.1 First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018
Pathogenic (Mar 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Urofacial syndrome type 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV001752510.2 First in ClinVar: Jul 18, 2021 Last updated: Dec 31, 2022
Likely pathogenic (Oct 18, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004167718.1 First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023	Comment: Frameshift variant predicted to result in the deletion of the last 104 amino acids, replaced with 125 incorrect amino acids; This variant is associated with … (more) Frameshift variant predicted to result in the deletion of the last 104 amino acids, replaced with 125 incorrect amino acids; This variant is associated with the following publications: (PMID: 20560209, 11446407, 31589614, 35812751, 20560210) (less)
Pathogenic (May 21, 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: SCV001414867.3 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 20560209‚ 20560210 Comment: Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, … (more) Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 84). This premature translational stop signal has been observed in individuals with urofacial syndrome (PMID: 20560209, 20560210). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs397515338, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Asn489Profs*126) in the HPSE2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 104 amino acid(s) of the HPSE2 protein. (less)
Likely pathogenic (Dec 13, 2022)	criteria provided, single submitter (Accession Criteria ClinVar Biomnis) Method: clinical testing	Urofacial syndrome type 1 Affected status: yes Allele origin: paternal	Eurofins-Biomnis Accession: SCV003935116.1 First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023
Pathogenic (Dec 11, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Urofacial syndrome type 1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002025028.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jun 11, 2010)	no assertion criteria provided Method: literature only	UROFACIAL SYNDROME 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000020247.3 First in ClinVar: Apr 04, 2013 Last updated: Apr 21, 2017	Publications: PubMed (3) PubMed: 20560209‚ 11446407‚ 20560210 Comment on evidence: In affected individuals with urofacial syndrome (UFS1; 236730) from 2 United States pedigrees with a common Irish heritage, Pang et al. (2010) identified homozygosity for … (more) In affected individuals with urofacial syndrome (UFS1; 236730) from 2 United States pedigrees with a common Irish heritage, Pang et al. (2010) identified homozygosity for a 2-bp deletion (1465delAA) in exon 10 of the HPSE2 gene, predicted to cause a frameshift resulting in a larger protein of 613 amino acids with a completely different sequence for the last 125 residues. In 2 Irish sisters with urofacial syndrome, originally reported by Garcia-Minaur et al. (2001), Daly et al. (2010) identified homozygosity for the 1465delAA mutation; Daly et al. (2010) predicted that the frameshift would result in nonsense-mediated decay or in a readily-degraded unfolded protein. The sisters had strikingly different presentations: one was severely affected from childhood and underwent multiple urologic surgeries, whereas the other was diagnosed only at age 25 years when she accompanied her sister to the urologic clinic. Their parents were heterozygous for the mutation, which was not found in 96 European controls. (less)
not provided (-)	no classification provided Method: literature only	Urofacial syndrome type 1 Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000086986.3 First in ClinVar: Oct 02, 2013 Last updated: Oct 29, 2022	Publications: PubMed (2) PubMed: 20560209‚ 20560210 Bookshelf: NBK154138 Bookshelf: NBK154138

Comment:

Frameshift variant predicted to result in the deletion of the last 104 amino acids, replaced with 125 incorrect amino acids; This variant is associated with the following publications: (PMID: 20560209, 11446407, 31589614, 35812751, 20560210)

Comment:

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 84). This premature translational stop signal has been observed in individuals with urofacial syndrome (PMID: 20560209, 20560210). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs397515338, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Asn489Profs*126) in the HPSE2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 104 amino acid(s) of the HPSE2 protein.

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
Urofacial Syndrome.	Adam MP	-	2023	PMID: 23967498
Mutations in HPSE2 cause urofacial syndrome.	Daly SB	American journal of human genetics	2010	PMID: 20560210
Loss-of-function mutations in HPSE2 cause the autosomal recessive urofacial syndrome.	Pang J	American journal of human genetics	2010	PMID: 20560209
Three new European cases of urofacial (Ochoa) syndrome.	Garcia-Minaur S	Clinical dysmorphology	2001	PMID: 11446407

Text-mined citations for rs397515338 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_021828.5(HPSE2):c.1465_1466del (p.Asn489fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397515338 ...