NM_000195.5(HPS1):c.972dup (p.Met325fs) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 24, 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:: RCV000520943.9

Allele description [Variation Report for NM_000195.5(HPS1):c.972dup (p.Met325fs)]

NM_000195.5(HPS1):c.972dup (p.Met325fs)

Genes:

MIR4685:microRNA 4685 [Gene - HGNC]
HPS1:HPS1 biogenesis of lysosomal organelles complex 3 subunit 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

10q24.2

Genomic location:

Preferred name:

NM_000195.5(HPS1):c.972dup (p.Met325fs)

Other names:

p.Met325HisfsX128; NM_000195.5(HPS1):c.972dup; p.Met325fs

HGVS:

NC_000010.11:g.98427237dup
NG_009646.1:g.24718dup
NM_000195.5:c.972dupMANE SELECT
NM_001311345.2:c.-1dup
NM_001322476.2:c.972dup
NM_001322477.2:c.972dup
NM_001322478.2:c.873dup
NM_001322479.2:c.873dup
NM_001322480.2:c.711dup
NM_001322481.2:c.711dup
NM_001322482.2:c.612dup
NM_001322483.2:c.603dup
NM_001322484.2:c.603dup
NM_001322485.2:c.504dup
NM_001322487.2:c.-1dup
NM_001322489.2:c.-1dup
NP_000186.2:p.Met325fs
NP_001298274.1:p.Met1fs
NP_001309405.1:p.Met325fs
NP_001309406.1:p.Met325fs
NP_001309407.1:p.Met292fs
NP_001309408.1:p.Met292fs
NP_001309409.1:p.Met238fs
NP_001309410.1:p.Met238fs
NP_001309411.1:p.Met205fs
NP_001309412.1:p.Met202fs
NP_001309413.1:p.Met202fs
NP_001309414.1:p.Met169fs
NP_001309416.1:p.Met1fs
NP_001309418.1:p.Met1fs
LRG_562t1:c.972dup
LRG_562:g.24718dup
LRG_562p1:p.Met325fs
NC_000010.10:g.100186986_100186987insG
NC_000010.10:g.100186994dup
NM_000195.2:c.972dupC
NM_000195.3:c.972dup
NM_000195.3:c.972dupC
NM_000195.4:c.972dup
NM_000195.5:c.972dupCMANE SELECT

Protein change:

M169fs

Links:

OMIM: 604982.0002; dbSNP: rs281865082

NCBI 1000 Genomes Browser:

rs281865082

Molecular consequence:

NM_000195.5:c.972dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001311345.2:c.-1dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322476.2:c.972dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322477.2:c.972dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322478.2:c.873dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322479.2:c.873dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322480.2:c.711dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322481.2:c.711dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322482.2:c.612dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322483.2:c.603dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322484.2:c.603dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322485.2:c.504dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322487.2:c.-1dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001322489.2:c.-1dup - frameshift variant - [Sequence Ontology: SO:0001589]

Functional consequence:

variation affecting RNA [Variation Ontology: 0297]

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
SCV000616745	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 21, 2019)	germline	clinical testing	Citation Link,
SCV001206311	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12442288, 8896559, 14510955, 15952982, 16185271, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000616745

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Oct 21, 2019)

germline

clinical testing

Citation Link,

SCV001206311

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 24, 2024)

germline

clinical testing

PubMed (6)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Hermansky-Pudlak syndrome type 1: gene organization, novel mutations, and clinical-molecular review of non-Puerto Rican cases.

Hermos CR, Huizing M, Kaiser-Kupfer MI, Gahl WA.

Hum Mutat. 2002 Dec;20(6):482.

PubMed [citation]

PMID:: 12442288

Positional cloning of a gene for Hermansky-Pudlak syndrome, a disorder of cytoplasmic organelles.

Oh J, Bailin T, Fukai K, Feng GH, Ho L, Mao JI, Frenk E, Tamura N, Spritz RA.

Nat Genet. 1996 Nov;14(3):300-6.

PubMed [citation]

PMID:: 8896559

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000616745.4

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

Description

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 8896559, 8274781, 19729668, 30791930, 31229681, 30387913, 31141302, 9497254, 14510955, 16185271, 32581362, 31589614, 32725903)

#	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 Invitae, SCV001206311.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change creates a premature translational stop signal (p.Met325Hisfs*128) in the HPS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPS1 are known to be pathogenic (PMID: 12442288, 16185271). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Hermansky‚ÄìPudlak syndrome (PMID: 8896559, 14510955, 15952982, 16185271). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as insC974 and Pro324 frameshift. ClinVar contains an entry for this variant (Variation ID: 5278). For these reasons, this variant has been classified as Pathogenic.

#	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

Last Updated: May 7, 2024

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