VCV001068714.15 - ClinVar

NM_000195.5(HPS1):c.1925del (p.Gly642fs)

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.

(5)

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_000195.5(HPS1):c.1925del (p.Gly642fs)

Variation ID: 1068714 Accession: VCV001068714.15

Type and length

Deletion, 1 bp

Location

Cytogenetic: 10q24.2 10: 98418190 (GRCh38) [ NCBI UCSC ] 10: 100177947 (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	May 10, 2021	Nov 24, 2024	Oct 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000195.5:c.1925del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000186.2:p.Gly642fs	frameshift
NM_000195.3:c.1925delG
NM_000195.4:c.1925delG
NM_001311345.2:c.953del	NP_001298274.1:p.Gly318fs	frameshift
NM_001322476.2:c.1925del	NP_001309405.1:p.Gly642fs	frameshift
NM_001322477.2:c.1925del	NP_001309406.1:p.Gly642fs	frameshift
NM_001322478.2:c.1826del	NP_001309407.1:p.Gly609fs	frameshift
NM_001322479.2:c.1826del	NP_001309408.1:p.Gly609fs	frameshift
NM_001322480.2:c.1664del	NP_001309409.1:p.Gly555fs	frameshift
NM_001322481.2:c.1664del	NP_001309410.1:p.Gly555fs	frameshift
NM_001322482.2:c.1565del	NP_001309411.1:p.Gly522fs	frameshift
NM_001322483.2:c.1556del	NP_001309412.1:p.Gly519fs	frameshift
NM_001322484.2:c.1556del	NP_001309413.1:p.Gly519fs	frameshift
NM_001322485.2:c.1457del	NP_001309414.1:p.Gly486fs	frameshift
NM_001322487.2:c.953del	NP_001309416.1:p.Gly318fs	frameshift
NM_001322489.2:c.953del	NP_001309418.1:p.Gly318fs	frameshift
NC_000010.11:g.98418192del
NC_000010.10:g.100177949del
NG_009646.1:g.33758del
LRG_562:g.33758del
LRG_562t1:c.1925del	LRG_562p1:p.Gly642fs

... more HGVS ... less HGVS

Protein change

G318fs, G486fs, G519fs, G522fs, G555fs, G609fs, G642fs

Other names

p.Gly642Glufs*83

Canonical SPDI

NC_000010.11:98418189:CCC:CC

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

dbSNP: rs2136083690 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.
HPS1		-	-	GRCh38 GRCh37	1099	1133

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/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 31, 2024	RCV001380350.14
Hermansky-Pudlak syndrome 1	Likely pathogenic (1)	criteria provided, single submitter	Oct 21, 2023	RCV003469647.1
HPS1-related disorder	Likely pathogenic (1)	no assertion criteria provided	Sep 17, 2024	RCV004754745.1

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.
Likely pathogenic (Oct 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hermansky-Pudlak syndrome 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004199920.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (May 07, 2021)	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: SCV001578354.4 First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 30387913‚ 19665357 Comment: For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the HPS1 protein. Other variant(s) that result in … (more) For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the HPS1 protein. Other variant(s) that result in a similarly extended protein product (p.Tyr645Thrfs80) have been determined to be pathogenic (PMID: 30387913, 19665357). This suggests that these extensions are likely to be causative of disease. This variant has not been reported in the literature in individuals with HPS1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the HPS1 gene (p.Gly642Glufs83). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 59 amino acid(s) of the HPS1 protein and extend the protein by 23 additional amino acid residues. (less)
Likely pathogenic (Oct 31, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001789335.5 First in ClinVar: Aug 21, 2021 Last updated: Nov 10, 2024	Comment: Has not been previously published as pathogenic or benign to our knowledge; Frameshift variant predicted to result in abnormal protein length as the last 59 … (more) Has not been previously published as pathogenic or benign to our knowledge; Frameshift variant predicted to result in abnormal protein length as the last 59 amino acids are replaced with 82 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD) (less)
Likely pathogenic (Apr 03, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005413955.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (3) PubMed: 19665357‚ 30387913‚ 32725903 Comment: PM2_moderate, PVS1_strong Number of individuals with the variant: 1
Likely pathogenic (Sep 17, 2024)	no assertion criteria provided Method: clinical testing	HPS1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005363046.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The HPS1 c.1925delG variant is predicted to result in a frameshift and premature protein termination (p.Gly642Glufs83). XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX which is predicted to result in a frameshift … (more) The HPS1 c.1925delG variant is predicted to result in a frameshift and premature protein termination (p.Gly642Glufs83). XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX which is predicted to result in a frameshift and extension of the normal open reading frame (p.Gly642Glufs83) (the canonical stop codon is at position p.701). To our knowledge, this variant has not been reported in the literature. However, this variant is similar in form and gene position to other reported variants (c.1887delC,p.Val630Serfs95; c.1932delC,p.Tyr645Thrfs*80) in individuals with Oculocutaneous albinism or Hermansky‐Pudlak syndrome (Wei et al. 2011. PubMed ID: 21458243; Wei et al. 2018. PubMed ID: 30387913). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1068714/). Taken together, this variant is interpreted as likely pathogenic. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the HPS1 protein. Other variant(s) that result in a similarly extended protein product (p.Tyr645Thrfs*80) have been determined to be pathogenic (PMID: 30387913, 19665357). This suggests that these extensions are likely to be causative of disease. This variant has not been reported in the literature in individuals with HPS1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the HPS1 gene (p.Gly642Glufs*83). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 59 amino acid(s) of the HPS1 protein and extend the protein by 23 additional amino acid residues.

Comment:

Has not been previously published as pathogenic or benign to our knowledge; Frameshift variant predicted to result in abnormal protein length as the last 59 amino acids are replaced with 82 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD)

Comment:

The HPS1 c.1925delG variant is predicted to result in a frameshift and premature protein termination (p.Gly642Glufs*83). XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX which is predicted to result in a frameshift and extension of the normal open reading frame (p.Gly642Glufs*83) (the canonical stop codon is at position p.701). To our knowledge, this variant has not been reported in the literature. However, this variant is similar in form and gene position to other reported variants (c.1887delC,p.Val630Serfs*95; c.1932delC,p.Tyr645Thrfs*80) in individuals with Oculocutaneous albinism or Hermansky‐Pudlak syndrome (Wei et al. 2011. PubMed ID: 21458243; Wei et al. 2018. PubMed ID: 30387913). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1068714/). Taken together, this variant is interpreted as likely 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
Genetic variants and mutational spectrum of Chinese Hermansky-Pudlak syndrome patients.	Liu T	Pigment cell & melanoma research	2021	PMID: 32725903
Instability of BLOC-2 and BLOC-3 in Chinese patients with Hermansky-Pudlak syndrome.	Wei A	Pigment cell & melanoma research	2019	PMID: 30387913
The first case report of a Chinese Hermansky-Pudlak syndrome patient with a novel mutation on HPS1 gene.	Wei A	Journal of dermatological science	2009	PMID: 19665357

Text-mined citations for rs2136083690 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000195.5(HPS1):c.1925del (p.Gly642fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2136083690 ...