VCV002146173.3 - ClinVar

NM_000081.4(LYST):c.10062_10063del (p.Ile3354fs)

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.

(2)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000081.4(LYST):c.10062_10063del (p.Ile3354fs)

Variation ID: 2146173 Accession: VCV002146173.3

Type and length

Deletion, 2 bp

Location

Cytogenetic: 1q42.3 1: 235709171-235709172 (GRCh38) [ NCBI UCSC ] 1: 235872471-235872472 (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	Feb 8, 2023	May 1, 2024	Jul 5, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000081.4:c.10062_10063del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000072.2:p.Ile3354fs	frameshift
NM_000081.2:c.10062_10063delCT
NM_001301365.1:c.10062_10063del	NP_001288294.1:p.Ile3354fs	frameshift
NC_000001.11:g.235709172_235709173del
NC_000001.10:g.235872472_235872473del
NG_007397.1:g.179469_179470del
NG_082387.1:g.1029_1030del
LRG_143:g.179469_179470del
LRG_143t1:c.10061_10062del	LRG_143p1:p.Ile3354Metfs
LRG_143t2:c.10062_10063del	LRG_143p2:p.Ile3354fs

... more HGVS ... less HGVS

Protein change

I3354fs

Other names

Canonical SPDI

NC_000001.11:235709170:AGA:A

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.

Links

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.
LOC126806063	-	-	-	GRCh38	-	83
LYST		-	-	GRCh38 GRCh37	3394	3532

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.
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jul 5, 2022	RCV003066995.2
Chédiak-Higashi syndrome	Pathogenic (1)	criteria provided, single submitter	Jan 26, 2022	RCV003066994.3

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.
Pathogenic (Jan 26, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Chédiak-Higashi syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003454492.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 9215679‚ 11857544 Comment: For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with LYST-related conditions. … (more) For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with LYST-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile3354Metfs*5) in the LYST gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LYST are known to be pathogenic (PMID: 9215679, 11857544). (less)
Pathogenic (Jul 05, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003632571.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Comment: The c.10062_10063delCT (p.I3354Mfs5) alteration, located in exon 44 (coding exon 42) of the LYST gene, consists of a deletion of 2 nucleotides from position 10062 … (more) The c.10062_10063delCT (p.I3354Mfs5) alteration, located in exon 44 (coding exon 42) of the LYST gene, consists of a deletion of 2 nucleotides from position 10062 to 10063, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as pathogenic. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with LYST-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile3354Metfs*5) in the LYST gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LYST are known to be pathogenic (PMID: 9215679, 11857544).

Comment:

The c.10062_10063delCT (p.I3354Mfs*5) alteration, located in exon 44 (coding exon 42) of the LYST gene, consists of a deletion of 2 nucleotides from position 10062 to 10063, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as pathogenic.

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

Title	Author	Journal	Year	Link
Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome.	Karim MA	American journal of medical genetics	2002	PMID: 11857544
Mutations in the Chediak-Higashi syndrome gene (CHS1) indicate requirement for the complete 3801 amino acid CHS protein.	Karim MA	Human molecular genetics	1997	PMID: 9215679

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000081.4(LYST):c.10062_10063del (p.Ile3354fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...