VCV000827680.4 - ClinVar

NM_012388.4(BLOC1S6):c.200C>G (p.Ser67Ter)

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.

(3)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_012388.4(BLOC1S6):c.200C>G (p.Ser67Ter)

Variation ID: 827680 Accession: VCV000827680.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q21.1 15: 45592252 (GRCh38) [ NCBI UCSC ] 15: 45884450 (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	Mar 26, 2020	Aug 11, 2024	Oct 19, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_012388.4:c.200C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_036520.1:p.Ser67Ter	nonsense
NM_001311255.1:c.215C>G	NP_001298184.1:p.Ser72Ter	nonsense
NM_001311256.1:c.215C>G	NP_001298185.1:p.Ser72Ter	nonsense
NR_132350.1:n.355C>G		non-coding transcript variant
NR_132351.2:n.265C>G		non-coding transcript variant
NR_132352.2:n.265C>G		non-coding transcript variant
NR_132356.2:n.223C>G		non-coding transcript variant
NR_132357.2:n.223C>G		non-coding transcript variant
NC_000015.10:g.45592252C>G
NC_000015.9:g.45884450C>G
NG_028194.2:g.10034C>G
LRG_883:g.10034C>G
LRG_883t1:c.200C>G

... more HGVS ... less HGVS

Protein change

S67*, S72*

Other names

Canonical SPDI

NC_000015.10:45592251:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

protein truncation; Variation Ontology [ VariO:0015]

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

OMIM: 604310.0003 dbSNP: rs772475341 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.
BLOC1S6		-	-	GRCh38 GRCh37	184	201

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 9	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 19, 2023	RCV001027539.6

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.
Pathogenic (Oct 19, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hermansky-Pudlak syndrome 9 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002965327.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 10610180‚ 21665000‚ 22461475‚ 32245340 Comment: This sequence change creates a premature translational stop signal (p.Ser67) in the BLOC1S6 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Ser67) in the BLOC1S6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BLOC1S6 are known to be pathogenic (PMID: 10610180, 21665000, 22461475). This variant is present in population databases (rs772475341, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 32245340). ClinVar contains an entry for this variant (Variation ID: 827680). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Feb 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hermansky-Pudlak syndrome 9 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Laboratoire de Génétique Moléculaire, CHU Bordeaux Accession: SCV001162834.1 First in ClinVar: Mar 26, 2020 Last updated: Mar 26, 2020	Comment: Patient is having oculocutaneous albinism and severe defect of platelets dense bodies highly suggesting of Hermansky-Pudlak Syndrome. Variant in trans of another variant classified Likely … (more) Patient is having oculocutaneous albinism and severe defect of platelets dense bodies highly suggesting of Hermansky-Pudlak Syndrome. Variant in trans of another variant classified Likely Pathogenic upon ACMG classification. Each parent has one variant. (less) Indication for testing: Oculocutaneous albinism Age: 0-9 years Sex: female Geographic origin: Syria
Pathogenic (Aug 06, 2024)	no assertion criteria provided Method: literature only	HERMANSKY-PUDLAK SYNDROME 9 Affected status: not provided Allele origin: germline	OMIM Accession: SCV005184310.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Publications: PubMed (1) PubMed: 32245340 Comment on evidence: In a 2.5-year-old Syrian girl with Hermansky-Pudlak syndrome-9 (HPS9; 614171), Michaud et al. (2021) identified compound heterozygosity for mutations in the BLOC1S6 gene: a c.200C-G … (more) In a 2.5-year-old Syrian girl with Hermansky-Pudlak syndrome-9 (HPS9; 614171), Michaud et al. (2021) identified compound heterozygosity for mutations in the BLOC1S6 gene: a c.200C-G transversion (c.200C-G, NM_012388.3) in exon 2, resulting in a ser67-to-ter (S67X) substitution, and an insertion/deletion (c.319_320delGAinsAT) in exon 4, resulting in a glu107-to-met (E107M; 604310.0004) substitution. Her unaffected parents were each heterozygous for 1 of the mutations; the insertion/deletion was not found in the gnomAD database, whereas the nonsense mutation was present once, in heterozygosity. (less)

Comment:

This sequence change creates a premature translational stop signal (p.Ser67*) in the BLOC1S6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BLOC1S6 are known to be pathogenic (PMID: 10610180, 21665000, 22461475). This variant is present in population databases (rs772475341, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 32245340). ClinVar contains an entry for this variant (Variation ID: 827680). For these reasons, this variant has been classified as Pathogenic.

Comment:

Patient is having oculocutaneous albinism and severe defect of platelets dense bodies highly suggesting of Hermansky-Pudlak Syndrome. Variant in trans of another variant classified Likely Pathogenic upon ACMG classification. Each parent has one variant.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
protein truncation (VariO:0015)			Laboratoire de Génétique Moléculaire, CHU Bordeaux Accession: SCV001162834.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A new case with Hermansky-Pudlak syndrome type 9, a rare cause of syndromic albinism with severe defect of platelets dense bodies.	Michaud V	Platelets	2021	PMID: 32245340
Exome sequencing reveals a pallidin mutation in a Hermansky-Pudlak-like primary immunodeficiency syndrome.	Badolato R	Blood	2012	PMID: 22461475
A BLOC-1 mutation screen reveals that PLDN is mutated in Hermansky-Pudlak Syndrome type 9.	Cullinane AR	American journal of human genetics	2011	PMID: 21665000
The pallid gene encodes a novel, syntaxin 13-interacting protein involved in platelet storage pool deficiency.	Huang L	Nature genetics	1999	PMID: 10610180

Text-mined citations for rs772475341 ...

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_012388.4(BLOC1S6):c.200C>G (p.Ser67Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs772475341 ...