VCV000497910.28 - ClinVar

NM_012092.4(ICOS):c.451G>C (p.Val151Leu)

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.

(7)

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.

Conflicting classifications of pathogenicity
Uncertain significance(3); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_012092.4(ICOS):c.451G>C (p.Val151Leu)

Variation ID: 497910 Accession: VCV000497910.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q33.2 2: 203956715 (GRCh38) [ NCBI UCSC ] 2: 204821438 (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	Apr 2, 2018	Oct 8, 2024	Mar 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_012092.4:c.451G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_036224.1:p.Val151Leu	missense
NC_000002.12:g.203956715G>C
NC_000002.11:g.204821438G>C
NG_011586.1:g.24936G>C
LRG_65:g.24936G>C
LRG_65t1:c.451G>C	LRG_65p1:p.Val151Leu

... more HGVS ... less HGVS

Protein change

V151L

Other names

Canonical SPDI

NC_000002.12:203956714:G:C

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.

0.00180 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00180

The Genome Aggregation Database (gnomAD) 0.00226

1000 Genomes Project 30x 0.00234

Trans-Omics for Precision Medicine (TOPMed) 0.00244

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00277

Links

ClinGen: CA2067284 dbSNP: rs76778263 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.
ICOS		-	-	GRCh38 GRCh37	172	208

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.
not provided	Uncertain significance (1)	criteria provided, single submitter	Oct 26, 2016	RCV000591514.7
Immunodeficiency, common variable, 1	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Mar 26, 2024	RCV000999898.24
ICOS-related disorder	Likely benign (1)	no assertion criteria provided	Jan 31, 2024	RCV003925776.2

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 (Oct 26, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000702664.2 First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ICOS Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Immunodeficiency, common variable, 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001298077.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely benign (Jan 26, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Immunodeficiency, common variable, 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001118112.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Likely benign (Sep 06, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Immunodeficiency, common variable, 1 Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000884021.3 First in ClinVar: Apr 02, 2018 Last updated: Feb 20, 2024
Uncertain significance (Jan 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency, common variable, 1 Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV003920034.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Comment: This variant has been reported in the literature in 2 individuals with a clinical suspicion of immunodeficiency (1 as a homozygote, segregating with disease in … (more) This variant has been reported in the literature in 2 individuals with a clinical suspicion of immunodeficiency (1 as a homozygote, segregating with disease in 1 affected relative and 1 as a heterozygote (Abolhassani 2019 PMID:29921932, Bisgin 2021 PMID:33859323). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.6% [256/41450] including 1 homozygote; https://gnomad.broadinstitute.org/variant/2-203956715-G-C?dataset=gnomad_r3). This variant is present in ClinVar, with classifications ranging from Variant of Uncertain Significance to Likely Benign (Variation ID: 497910). Evolutionary conservation and computational prediction tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
Likely benign (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency, common variable, 1 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806639.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Likely benign (Jan 31, 2024)	no assertion criteria provided Method: clinical testing	ICOS-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004756255.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant has been reported in the literature in 2 individuals with a clinical suspicion of immunodeficiency (1 as a homozygote, segregating with disease in 1 affected relative and 1 as a heterozygote (Abolhassani 2019 PMID:29921932, Bisgin 2021 PMID:33859323). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.6% [256/41450] including 1 homozygote; https://gnomad.broadinstitute.org/variant/2-203956715-G-C?dataset=gnomad_r3). This variant is present in ClinVar, with classifications ranging from Variant of Uncertain Significance to Likely Benign (Variation ID: 497910). Evolutionary conservation and computational prediction tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ICOS	-	-	-	-

Text-mined citations for rs76778263 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_012092.4(ICOS):c.451G>C (p.Val151Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs76778263 ...