NM_000195.5(HPS1):c.1096C>A (p.Pro366Thr) AND Hermansky-Pudlak syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Nov 29, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000851655.5

Allele description [Variation Report for NM_000195.5(HPS1):c.1096C>A (p.Pro366Thr)]

NM_000195.5(HPS1):c.1096C>A (p.Pro366Thr)

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.1096C>A (p.Pro366Thr)

Other names:

NM_000195.5(HPS1):c.1096C>A; p.Pro366Thr

HGVS:

NC_000010.11:g.98425877G>T
NG_009646.1:g.26071C>A
NM_000195.5:c.1096C>AMANE SELECT
NM_001311345.2:c.124C>A
NM_001322476.2:c.1096C>A
NM_001322477.2:c.1096C>A
NM_001322478.2:c.997C>A
NM_001322479.2:c.997C>A
NM_001322480.2:c.835C>A
NM_001322481.2:c.835C>A
NM_001322482.2:c.736C>A
NM_001322483.2:c.727C>A
NM_001322484.2:c.727C>A
NM_001322485.2:c.628C>A
NM_001322487.2:c.124C>A
NM_001322489.2:c.124C>A
NP_000186.2:p.Pro366Thr
NP_001298274.1:p.Pro42Thr
NP_001309405.1:p.Pro366Thr
NP_001309406.1:p.Pro366Thr
NP_001309407.1:p.Pro333Thr
NP_001309408.1:p.Pro333Thr
NP_001309409.1:p.Pro279Thr
NP_001309410.1:p.Pro279Thr
NP_001309411.1:p.Pro246Thr
NP_001309412.1:p.Pro243Thr
NP_001309413.1:p.Pro243Thr
NP_001309414.1:p.Pro210Thr
NP_001309416.1:p.Pro42Thr
NP_001309418.1:p.Pro42Thr
LRG_562t1:c.1096C>A
LRG_562:g.26071C>A
LRG_562p1:p.Pro366Thr
NC_000010.10:g.100185634G>T
NM_000195.3:c.1096C>A
NM_000195.4:c.1096C>A

Protein change:

P210T

Links:

dbSNP: rs138771756

NCBI 1000 Genomes Browser:

rs138771756

Molecular consequence:

NM_000195.5:c.1096C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001311345.2:c.124C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322476.2:c.1096C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322477.2:c.1096C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322478.2:c.997C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322479.2:c.997C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322480.2:c.835C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322481.2:c.835C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322482.2:c.736C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322483.2:c.727C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322484.2:c.727C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322485.2:c.628C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322487.2:c.124C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322489.2:c.124C>A - missense variant - [Sequence Ontology: SO:0001583]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000899423	NIHR Bioresource Rare Diseases, University of Cambridge - ThromboGenomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 1, 2019)	unknown	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31064749
SCV002097058	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 29, 2021)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000899423

NIHR Bioresource Rare Diseases, University of Cambridge - ThromboGenomics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 1, 2019)

unknown

research

PubMed (2)
[See all records that cite these PMIDs]

SCV002097058

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 29, 2021)

germline

curation

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
European	unknown	yes	1	not provided	not provided	1	not provided	research

Citations

PubMed

Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.

Downes K, Megy K, Duarte D, Vries M, Gebhart J, Hofer S, Shamardina O, Deevi SVV, Stephens J, Mapeta R, Tuna S, Al Hasso N, Besser MW, Cooper N, Daugherty L, Gleadall N, Greene D, Haimel M, Martin H, Papadia S, Revel-Vilk S, Sivapalaratnam S, et al.

Blood. 2019 Dec 5;134(23):2082-2091. doi: 10.1182/blood.2018891192.

PubMed [citation]

PMID:: 31064749
PMCID:: PMC6993014

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

Details of each submission

From NIHR Bioresource Rare Diseases, University of Cambridge - ThromboGenomics, SCV000899423.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	European	1	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV002097058.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

The p.Pro366Thr variant in HPS1 has been reported in 1 individual with Hermansky-Pudlak syndrome (PMID: 31064749) and has been identified in 0.02% (4/24962) of African/African-American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs748106098). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 8626969) and has been interpreted as likely pathogenic by NIHR Bioresource Rare Diseases (University of Cambridge). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro366Thr variant is uncertain. ACMG/AMP Criteria applied: PM3_supporting, PP3 (Richards 2015).

#	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: Mar 30, 2024

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