VCV001684358.5 - ClinVar

NM_000195.5(HPS1):c.689G>A (p.Arg230His)

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.

(4)

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.

Uncertain significance

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.689G>A (p.Arg230His)

Variation ID: 1684358 Accession: VCV001684358.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q24.2 10: 98430650 (GRCh38) [ NCBI UCSC ] 10: 100190407 (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 21, 2022	Aug 18, 2024	Aug 9, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000195.5:c.689G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000186.2:p.Arg230His	missense
NM_001311345.2:c.-185G>A		5 prime UTR
NM_001322476.2:c.689G>A	NP_001309405.1:p.Arg230His	missense
NM_001322477.2:c.689G>A	NP_001309406.1:p.Arg230His	missense
NM_001322478.2:c.689G>A	NP_001309407.1:p.Arg230His	missense
NM_001322479.2:c.689G>A	NP_001309408.1:p.Arg230His	missense
NM_001322480.2:c.428G>A	NP_001309409.1:p.Arg143His	missense
NM_001322481.2:c.428G>A	NP_001309410.1:p.Arg143His	missense
NM_001322482.2:c.428G>A	NP_001309411.1:p.Arg143His	missense
NM_001322483.2:c.320G>A	NP_001309412.1:p.Arg107His	missense
NM_001322484.2:c.320G>A	NP_001309413.1:p.Arg107His	missense
NM_001322485.2:c.320G>A	NP_001309414.1:p.Arg107His	missense
NM_001322487.2:c.-284G>A		5 prime UTR
NM_001322489.2:c.-185G>A		5 prime UTR
NM_001322490.2:c.571G>A	NP_001309419.1:p.Ala191Thr	missense
NM_001322491.2:c.689G>A	NP_001309420.1:p.Arg230His	missense
NM_001322492.2:c.571G>A	NP_001309421.1:p.Ala191Thr	missense
NM_182639.4:c.689G>A	NP_872577.1:p.Arg230His	missense
NC_000010.11:g.98430650C>T
NC_000010.10:g.100190407C>T
NG_009646.1:g.21298G>A
LRG_562:g.21298G>A
LRG_562t1:c.689G>A	LRG_562p1:p.Arg230His

... more HGVS ... less HGVS

Protein change

A191T, R107H, R143H, R230H

Other names

Canonical SPDI

NC_000010.11:98430649:C:T

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00006

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00016

Links

dbSNP: rs377752969 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	1097	1131

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.
Hermansky-Pudlak syndrome 1	Uncertain significance (2)	criteria provided, single submitter	-	RCV002245364.4
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 9, 2022	RCV003093961.3

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.
Uncertain significance (Aug 09, 2022)	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: SCV003524695.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 230 of the HPS1 protein (p.Arg230His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 230 of the HPS1 protein (p.Arg230His). This variant is present in population databases (rs377752969, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with HPS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1684358). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hermansky-Pudlak syndrome 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004100538.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023	Comment: The missense variant p.R230H in HPS1 (NM_000195.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The … (more) The missense variant p.R230H in HPS1 (NM_000195.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.R230H variant is observed in 7/25,022 (0.028%) alleles from individuals of Latino background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.In silico predictions are damaging and the residue is weakly conserved across residues. For these reasons, this variant has been classified as Uncertain Significance. The variant is present in 70% reads and hence zygosity is not confirmed. (less) Clinical Features: Failure to thrive (present) , Diarrhea (present) , Vomiting (present)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005190968.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024
Uncertain significance (-)	no assertion criteria provided Method: research	Hermansky-Pudlak syndrome 1 Affected status: yes Allele origin: unknown	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology Accession: SCV002515569.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022 Comment: Submitted to GoldVariant by Dr Marie-Christine Morel-Kopp from Northern Blood Research Centre, Sydney, Australia	Clinical Features: Pancytopenia (present)

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 230 of the HPS1 protein (p.Arg230His). This variant is present in population databases (rs377752969, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with HPS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1684358). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The missense variant p.R230H in HPS1 (NM_000195.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.R230H variant is observed in 7/25,022 (0.028%) alleles from individuals of Latino background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.In silico predictions are damaging and the residue is weakly conserved across residues. For these reasons, this variant has been classified as Uncertain Significance. The variant is present in 70% reads and hence zygosity is not confirmed.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs377752969 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000195.5(HPS1):c.689G>A (p.Arg230His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs377752969 ...