VCV000333435.31 - ClinVar

NM_032977.4(CASP10):c.1216A>T (p.Ile406Leu)

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(1); Benign(2); 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_032977.4(CASP10):c.1216A>T (p.Ile406Leu)

Variation ID: 333435 Accession: VCV000333435.31

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q33.1 2: 201209363 (GRCh38) [ NCBI UCSC ] 2: 202074086 (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	Oct 20, 2024	Mar 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_032977.4:c.1216A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_116759.2:p.Ile406Leu	missense
NM_001206524.2:c.1015A>T	NP_001193453.1:p.Ile339Leu	missense
NM_001206542.2:c.1087A>T	NP_001193471.1:p.Ile363Leu	missense
NM_001230.5:c.1087A>T	NP_001221.2:p.Ile363Leu	missense
NM_032974.5:c.1216A>T	NP_116756.2:p.Ile406Leu	missense
NM_032976.4:c.*302A>T		3 prime UTR
NC_000002.12:g.201209363A>T
NC_000002.11:g.202074086A>T
NG_007265.1:g.31232A>T
LRG_33:g.31232A>T
LRG_33t1:c.1216A>T	LRG_33p1:p.Ile406Leu
	Q92851:p.Ile406Leu

... more HGVS ... less HGVS

Protein change

I406L, I363L, I339L

Other names

Canonical SPDI

NC_000002.12:201209362:A: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.

0.00479 (T)

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

Trans-Omics for Precision Medicine (TOPMed) 0.00232

The Genome Aggregation Database (gnomAD) 0.00307

The Genome Aggregation Database (gnomAD), exomes 0.00453

1000 Genomes Project 0.00479

1000 Genomes Project 30x 0.00484

Exome Aggregation Consortium (ExAC) 0.00494

Links

ClinGen: CA2053200 UniProtKB: Q92851#VAR_037429 dbSNP: rs80358239 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.
CASP10		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	520	554

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.
Autoimmune lymphoproliferative syndrome type 2A	Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jan 26, 2024	RCV000378446.21
Hypomyelination and Congenital Cataract	Benign (1)	criteria provided, single submitter	-	RCV001258256.10
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Mar 1, 2024	RCV000440171.25

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.
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Autoimmune lymphoproliferative syndrome type 2A Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000426105.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 16446975 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely Benign (Jan 06, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000511682.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: Converted during submission to Likely benign.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hypomyelination and Congenital Cataract (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435170.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Publications: PubMed (2) PubMed: 16446975‚ 22995991 Comment: The heterozygous p.Ile406Leu variant in CASP10 has been identified in 2 individuals with autoimmune lymphoproliferative syndrome (PMID: 16446975), but has also been identified in >1% … (more) The heterozygous p.Ile406Leu variant in CASP10 has been identified in 2 individuals with autoimmune lymphoproliferative syndrome (PMID: 16446975), but has also been identified in >1% of South Asian chromosomes and 9 homozygotes by ExAC (http://gnomad.broadinstitute.org/). This variant has also been identified in a heterozygous individual and a homozygous individual who have not been reported to have disease (PMID: 22995991). In vitro functional studies provide some evidence that the p.Ile406Leu variant may slightly impact protein function (PMID: 16446975). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal dominant autoimmune lymphoproliferative syndrome. (less)
Likely benign (Jan 26, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autoimmune lymphoproliferative syndrome type 2A Autoimmune lymphoproliferative syndrome type 2A Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000644013.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 28492532
Uncertain significance (Mar 08, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002107205.2 First in ClinVar: Mar 28, 2022 Last updated: Mar 04, 2023	Comment: Published in vitro functional studies showed that this variant conferred significant resistance to apoptosis in transfected cells which was even stronger when co-transfected with wild-type … (more) Published in vitro functional studies showed that this variant conferred significant resistance to apoptosis in transfected cells which was even stronger when co-transfected with wild-type CASP10 indicating a probable dominant negative effect (Zhu et al., 2006); This variant is associated with the following publications: (PMID: 22995991, 27535533, 16446975, 32599613, 27378136, 31309545) (less)
Benign (Mar 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004011287.12 First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024	Comment: CASP10: BP4, BS1, BS2 Number of individuals with the variant: 7
not provided (-)	no classification provided Method: literature only	Autoimmune lymphoproliferative syndrome type 2A Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV002032180.2 First in ClinVar: Dec 14, 2021 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1108 BookShelf: NBK1108

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

The heterozygous p.Ile406Leu variant in CASP10 has been identified in 2 individuals with autoimmune lymphoproliferative syndrome (PMID: 16446975), but has also been identified in >1% of South Asian chromosomes and 9 homozygotes by ExAC (http://gnomad.broadinstitute.org/). This variant has also been identified in a heterozygous individual and a homozygous individual who have not been reported to have disease (PMID: 22995991). In vitro functional studies provide some evidence that the p.Ile406Leu variant may slightly impact protein function (PMID: 16446975). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal dominant autoimmune lymphoproliferative syndrome.

Comment:

Published in vitro functional studies showed that this variant conferred significant resistance to apoptosis in transfected cells which was even stronger when co-transfected with wild-type CASP10 indicating a probable dominant negative effect (Zhu et al., 2006); This variant is associated with the following publications: (PMID: 22995991, 27535533, 16446975, 32599613, 27378136, 31309545)

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
Autoimmune Lymphoproliferative Syndrome.	Adam MP	-	2017	PMID: 20301287
An informatics approach to analyzing the incidentalome.	Berg JS	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22995991
Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome.	Zhu S	Human genetics	2006	PMID: 16446975

Text-mined citations for rs80358239 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_032977.4(CASP10):c.1216A>T (p.Ile406Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80358239 ...