NM_032977.4(CASP10):c.853C>T (p.Leu285Phe) AND Autoimmune lymphoproliferative syndrome type 2A

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 24, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000008205.17

Allele description [Variation Report for NM_032977.4(CASP10):c.853C>T (p.Leu285Phe)]

NM_032977.4(CASP10):c.853C>T (p.Leu285Phe)

Gene:

CASP10:caspase 10 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q33.1

Genomic location:

Preferred name:

NM_032977.4(CASP10):c.853C>T (p.Leu285Phe)

HGVS:

NC_000002.12:g.201208114C>T
NG_007265.1:g.29983C>T
NM_001206524.2:c.722-956C>T
NM_001206542.2:c.724C>T
NM_001230.5:c.724C>T
NM_032974.5:c.853C>T
NM_032976.4:c.761C>T
NM_032977.4:c.853C>TMANE SELECT
NP_001193471.1:p.Leu242Phe
NP_001221.2:p.Leu242Phe
NP_116756.2:p.Leu285Phe
NP_116758.1:p.Pro254Leu
NP_116759.2:p.Leu285Phe
NP_116759.2:p.Leu285Phe
LRG_33t1:c.853C>T
LRG_33:g.29983C>T
LRG_33p1:p.Leu285Phe
NC_000002.11:g.202072837C>T
NM_032977.3:c.853C>T
Q92851:p.Leu285Phe

Protein change:

L242F; LEU285PHE

Links:

UniProtKB: Q92851#VAR_014071; OMIM: 601762.0001; dbSNP: rs17860403

NCBI 1000 Genomes Browser:

rs17860403

Molecular consequence:

NM_001206524.2:c.722-956C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001206542.2:c.724C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001230.5:c.724C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_032974.5:c.853C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_032976.4:c.761C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_032977.4:c.853C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autoimmune lymphoproliferative syndrome type 2A
Synonyms:: AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IIA; Autoimmune lymphoproliferative syndrome type 2
Identifiers:: MONDO: MONDO:0011383; MedGen: C1858968; Orphanet: 3261; OMIM: 603909

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000028412	OMIM	no assertion criteria provided	Pathogenic (Jul 9, 1999)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000041547	GeneReviews	no classification provided	not provided	germline	literature only
SCV001388324	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 24, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16446975, 27799292, 10412980, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000028412

OMIM

no assertion criteria provided

Pathogenic
(Jul 9, 1999)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000041547

GeneReviews

no classification provided

not provided

germline

literature only

SCV001388324

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 24, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome.

Zhu S, Hsu AP, Vacek MM, Zheng L, Schäffer AA, Dale JK, Davis J, Fischer RE, Straus SE, Boruchov D, Saulsbury FT, Lenardo MJ, Puck JM.

Hum Genet. 2006 Apr;119(3):284-94. Epub 2006 Jan 31.

PubMed [citation]

PMID:: 16446975

SUMO-Modified FADD Recruits Cytosolic Drp1 and Caspase-10 to Mitochondria for Regulated Necrosis.

Choi SG, Kim H, Jeong EI, Lee HJ, Park S, Lee SY, Lee HJ, Lee SW, Chung CH, Jung YK.

Mol Cell Biol. 2017 Jan 4;37(2). doi:pii: e00254-16. 10.1128/MCB.00254-16. Print 2017 Jan 15.

PubMed [citation]

PMID:: 27799292
PMCID:: PMC5214857

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000028412.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In an African American patient with ALPS2A (603909), Wang et al. (1999) identified a heterozygous 724C-T transition in the CASP10 gene, resulting in a leu242-to-phe (L242F) substitution (L285F in the longer CASP10 isoform). The proband's mother, who exhibited high levels of autoantibodies to nuclear antigens and defective lymphocyte apoptosis, also had the mutation. The proband's unaffected father and 2 sisters did not have the mutation. The mutation was not found in 200 normal chromosomes or in any patient with ALPS type I (601859).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000041547.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001388324.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Experimental studies have shown that this missense change affects CASP10 function (PMID: 10412980, 16446975, 27799292). 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 not expected to disrupt CASP10 protein function. ClinVar contains an entry for this variant (Variation ID: 7764). This missense change has been observed in individual(s) with clinical features of autoimmune lymphoproliferative syndrome (PMID: 10412980). This variant is present in population databases (rs17860403, gnomAD 0.03%). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 285 of the CASP10 protein (p.Leu285Phe). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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