NM_000195.5(HPS1):c.1925del (p.Gly642fs) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Oct 31, 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:: RCV001380350.14

Allele description [Variation Report for NM_000195.5(HPS1):c.1925del (p.Gly642fs)]

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

Gene:

HPS1:HPS1 biogenesis of lysosomal organelles complex 3 subunit 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

10q24.2

Genomic location:

Preferred name:

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

Other names:

p.Gly642Glufs*83

HGVS:

NC_000010.11:g.98418192del
NG_009646.1:g.33758del
NM_000195.5:c.1925delMANE SELECT
NM_001311345.2:c.953del
NM_001322476.2:c.1925del
NM_001322477.2:c.1925del
NM_001322478.2:c.1826del
NM_001322479.2:c.1826del
NM_001322480.2:c.1664del
NM_001322481.2:c.1664del
NM_001322482.2:c.1565del
NM_001322483.2:c.1556del
NM_001322484.2:c.1556del
NM_001322485.2:c.1457del
NM_001322487.2:c.953del
NM_001322489.2:c.953del
NP_000186.2:p.Gly642fs
NP_001298274.1:p.Gly318fs
NP_001309405.1:p.Gly642fs
NP_001309406.1:p.Gly642fs
NP_001309407.1:p.Gly609fs
NP_001309408.1:p.Gly609fs
NP_001309409.1:p.Gly555fs
NP_001309410.1:p.Gly555fs
NP_001309411.1:p.Gly522fs
NP_001309412.1:p.Gly519fs
NP_001309413.1:p.Gly519fs
NP_001309414.1:p.Gly486fs
NP_001309416.1:p.Gly318fs
NP_001309418.1:p.Gly318fs
LRG_562t1:c.1925del
LRG_562:g.33758del
LRG_562p1:p.Gly642fs
NC_000010.10:g.100177947del
NC_000010.10:g.100177949del
NM_000195.3:c.1925del
NM_000195.3:c.1925delG
NM_000195.4:c.1925delG

Protein change:

G318fs

Links:

dbSNP: rs2136083690

NCBI 1000 Genomes Browser:

rs2136083690

Molecular consequence:

NM_000195.5:c.1925del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001311345.2:c.953del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322476.2:c.1925del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322477.2:c.1925del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322478.2:c.1826del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322479.2:c.1826del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322480.2:c.1664del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322481.2:c.1664del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322482.2:c.1565del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322483.2:c.1556del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322484.2:c.1556del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322485.2:c.1457del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322487.2:c.953del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322489.2:c.953del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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
SCV001578354	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 7, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30387913, 19665357, 28492532
SCV001789335	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Oct 31, 2024)	germline	clinical testing	Citation Link,
SCV005413955	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 3, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19665357, 30387913, 32725903, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001578354

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 7, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001789335

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Oct 31, 2024)

germline

clinical testing

Citation Link,

SCV005413955

Mayo Clinic Laboratories, Mayo Clinic

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 3, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

The first case report of a Chinese Hermansky-Pudlak syndrome patient with a novel mutation on HPS1 gene.

Wei A, Lian S, Wang L, Li W.

J Dermatol Sci. 2009 Nov;56(2):130-2. doi: 10.1016/j.jdermsci.2009.07.007. Epub 2009 Aug 7. No abstract available.

PubMed [citation]

PMID:: 19665357

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001578354.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	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, SCV001789335.5

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

Description

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)

#	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

From Mayo Clinic Laboratories, Mayo Clinic, SCV005413955.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

PM2_moderate, PVS1_strong

#	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		1	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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