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NM_000195.5(HPS1):c.988-1G>T AND Hermansky-Pudlak syndrome

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Apr 4, 2023
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:
RCV001826175.3

Allele description [Variation Report for NM_000195.5(HPS1):c.988-1G>T]

NM_000195.5(HPS1):c.988-1G>T

Gene:
HPS1:HPS1 biogenesis of lysosomal organelles complex 3 subunit 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
10q24.2
Genomic location:
Preferred name:
NM_000195.5(HPS1):c.988-1G>T
HGVS:
  • NC_000010.11:g.98425986C>A
  • NG_009646.1:g.25962G>T
  • NM_000195.5:c.988-1G>TMANE SELECT
  • NM_001311345.2:c.16-1G>T
  • NM_001322476.2:c.988-1G>T
  • NM_001322477.2:c.988-1G>T
  • NM_001322478.2:c.889-1G>T
  • NM_001322479.2:c.889-1G>T
  • NM_001322480.2:c.727-1G>T
  • NM_001322481.2:c.727-1G>T
  • NM_001322482.2:c.628-1G>T
  • NM_001322483.2:c.619-1G>T
  • NM_001322484.2:c.619-1G>T
  • NM_001322485.2:c.520-1G>T
  • NM_001322487.2:c.16-1G>T
  • NM_001322489.2:c.16-1G>T
  • LRG_562t1:c.988-1G>T
  • LRG_562:g.25962G>T
  • NC_000010.10:g.100185743C>A
  • NM_000195.4:c.988-1G>T
Links:
dbSNP: rs764927038
NCBI 1000 Genomes Browser:
rs764927038
Molecular consequence:
  • NM_000195.5:c.988-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001311345.2:c.16-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001322476.2:c.988-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001322477.2:c.988-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001322478.2:c.889-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001322479.2:c.889-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001322480.2:c.727-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001322481.2:c.727-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001322482.2:c.628-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001322483.2:c.619-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001322484.2:c.619-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001322485.2:c.520-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001322487.2:c.16-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001322489.2:c.16-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:
Hermansky-Pudlak syndrome (HPS)
Synonyms:
Albinism with hemorrhagic diathesis and pigmented reticuloendothelial cells
Identifiers:
MONDO: MONDO:0019312; MedGen: C0079504; OMIM: PS203300

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002097059Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Nov 29, 2021)
germlinecuration

PubMed (1)
[See all records that cite this PMID]

SCV003928842Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Apr 4, 2023)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Hermansky-Pudlak syndrome type 1 in patients of Indian descent.

Vincent LM, Adams D, Hess RA, Ziegler SG, Tsilou E, Golas G, O'Brien KJ, White JG, Huizing M, Gahl WA.

Mol Genet Metab. 2009 Jul;97(3):227-33. doi: 10.1016/j.ymgme.2009.03.011. Epub 2009 Apr 2.

PubMed [citation]
PMID:
19398212
PMCID:
PMC2694228

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV002097059.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The c.988-1G>T variant in HPS1 has been reported in 1 individual, in the homozygous state, with Hermansky-Pudlak syndrome (PMID: 19398212), and has been identified in 0.0098% (3/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs764927038). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 1074133) and has been interpreted as pathogenic by Invitae. In vitro functional studies provide some evidence that the c.988-1G>T variant may slightly impact protein function (PMID: 19398212). However, these types of assays may not accurately represent biological function. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the HPS1 gene is an established disease mechanism in autosomal recessive Hermansky-Pudlak syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Hermansky-Pudlak syndrome. ACMG/AMP Criteria applied: PVS1_moderate, PM2_supporting, PM3_supporting, PS3_moderate (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003928842.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

Variant summary: HPS1 c.988-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. Experimental evidence have shown disruption of this splice site results in exon 12 skipping, leading to an inframe deletion of 56 amino acids from the encoded HPS1 protein (example: Vincent_2009). The variant allele was found at a frequency of 1.2e-05 in 251112 control chromosomes (gnomAD). c.988-1G>T has been reported in the literature in an individual affected with Hermansky-Pudlak Syndrome (example: Vincent_2009). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and allclassified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 17, 2024