VCV000296390.14 - ClinVar

NM_000081.4(LYST):c.6079G>C (p.Val2027Leu)

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.

(6)

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_000081.4(LYST):c.6079G>C (p.Val2027Leu)

Variation ID: 296390 Accession: VCV000296390.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q42.3 1: 235766121 (GRCh38) [ NCBI UCSC ] 1: 235929421 (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	Dec 6, 2016	Sep 16, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000081.4:c.6079G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000072.2:p.Val2027Leu	missense
NM_001301365.1:c.6079G>C	NP_001288294.1:p.Val2027Leu	missense
NC_000001.11:g.235766121C>G
NC_000001.10:g.235929421C>G
NG_007397.1:g.122520G>C
LRG_143:g.122520G>C
LRG_143t1:c.6079G>C	LRG_143p1:p.Val2027Leu
LRG_143t2:c.6079G>C	LRG_143p2:p.Val2027Leu

... more HGVS ... less HGVS

Protein change

V2027L

Other names

Canonical SPDI

NC_000001.11:235766120:C:G

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

ClinGen: CA1466465 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.
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.
Chédiak-Higashi syndrome	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Oct 13, 2022	RCV000337588.16
Susceptibility to severe COVID-19	Likely risk allele (1)	no assertion criteria provided	Jul 1, 2022	RCV003114467.4
not specified	Uncertain significance (1)	criteria provided, single submitter	Jul 31, 2024	RCV004701398.1

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 (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Chédiak-Higashi syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000355747.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Oct 13, 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: SCV001414644.5 First in ClinVar: Jul 16, 2020 Last updated: Nov 11, 2023	Comment: This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2027 of the LYST protein (p.Val2027Leu). … (more) This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2027 of the LYST protein (p.Val2027Leu). This variant is present in population databases (rs374351038, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with LYST-related conditions. ClinVar contains an entry for this variant (Variation ID: 296390). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LYST protein function. 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 (Aug 02, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Chédiak-Higashi syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003815207.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Jul 31, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005202247.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Publications: PubMed (1) PubMed: 33217554 Comment: Variant summary: LYST c.6079G>C (p.Val2027Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more) Variant summary: LYST c.6079G>C (p.Val2027Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250696 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LYST causing Chediak-Higashi Syndrome (5.6e-05 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, c.6079G>C has not been reported in the literature in individuals affected with Chediak-Higashi Syndrome. The following publication has been ascertained in the context of this evaluation (PMID: 33217554). ClinVar contains an entry for this variant (Variation ID: 296390). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (-)	no assertion criteria provided Method: research	Chédiak-Higashi syndrome Affected status: yes Allele origin: unknown	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology Accession: SCV002546494.1 First in ClinVar: Jul 13, 2022 Last updated: Jul 13, 2022 Comment: Submitted to GoldVariant by Dr Marie-Christine Morel-Kopp from Northern Blood Research Centre, Sydney, Australia	Clinical Features: Thrombocytopenia with bleeding history (present) , Refractory to Immune thrombocytopenia treatment (present)
Likely risk allele (Jul 01, 2022)	no assertion criteria provided Method: research	Susceptibility to severe COVID-19 Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV003798474.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2027 of the LYST protein (p.Val2027Leu). This variant is present in population databases (rs374351038, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with LYST-related conditions. ClinVar contains an entry for this variant (Variation ID: 296390). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LYST protein function. 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:

Variant summary: LYST c.6079G>C (p.Val2027Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250696 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LYST causing Chediak-Higashi Syndrome (5.6e-05 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, c.6079G>C has not been reported in the literature in individuals affected with Chediak-Higashi Syndrome. The following publication has been ascertained in the context of this evaluation (PMID: 33217554). ClinVar contains an entry for this variant (Variation ID: 296390). Based on the evidence outlined above, the variant was classified as uncertain significance.

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
A Next-Generation Sequencing Test for Severe Congenital Neutropenia: Utility in a Broader Clinicopathologic Spectrum of Disease.	McNulty SN	The Journal of molecular diagnostics : JMD	2021	PMID: 33217554

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.6079G>C (p.Val2027Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...