NM_000043.6(FAS):c.776T>C (p.Ile259Thr) AND Autoimmune lymphoproliferative syndrome type 1

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 10, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001067019.9

Allele description [Variation Report for NM_000043.6(FAS):c.776T>C (p.Ile259Thr)]

NM_000043.6(FAS):c.776T>C (p.Ile259Thr)

Gene:

FAS:Fas cell surface death receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q23.31

Genomic location:

Preferred name:

NM_000043.6(FAS):c.776T>C (p.Ile259Thr)

HGVS:

NC_000010.11:g.89014218T>C
NG_009089.2:g.28688T>C
NM_000043.6:c.776T>CMANE SELECT
NM_001320619.2:c.*99T>C
NM_152871.4:c.713T>C
NM_152872.4:c.*88T>C
NP_000034.1:p.Ile259Thr
NP_690610.1:p.Ile238Thr
LRG_134:g.28688T>C
NC_000010.10:g.90773975T>C
NM_000043.5:c.776T>C
NR_028033.4:n.683T>C
NR_028034.4:n.545T>C
NR_028035.4:n.608T>C
NR_028036.4:n.746T>C
NR_135313.2:n.663T>C
NR_135314.2:n.942T>C
NR_135315.2:n.695T>C

Protein change:

I238T

Links:

dbSNP: rs1848675068

NCBI 1000 Genomes Browser:

rs1848675068

Molecular consequence:

NM_001320619.2:c.*99T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_152872.4:c.*88T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000043.6:c.776T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_152871.4:c.713T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_028033.4:n.683T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_028034.4:n.545T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_028035.4:n.608T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_028036.4:n.746T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_135313.2:n.663T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_135314.2:n.942T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_135315.2:n.695T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Autoimmune lymphoproliferative syndrome type 1 (ALPS)
Synonyms:: Autoimmune lymphoproliferative syndrome type 1, autosomal dominant; AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE I, AUTOSOMAL DOMINANT
Identifiers:: MONDO: MONDO:0011158; MedGen: C1328840; Orphanet: 3261; OMIM: 601859

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001232048	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10515860, 12657942, 28492532
SCV004037578	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001232048

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 10, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004037578

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

maternal

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Lymphoproliferative syndrome with autoimmunity: A possible genetic basis for dominant expression of the clinical manifestations.

Rieux-Laucat F, Blachère S, Danielan S, De Villartay JP, Oleastro M, Solary E, Bader-Meunier B, Arkwright P, Pondaré C, Bernaudin F, Chapel H, Nielsen S, Berrah M, Fischer A, Le Deist F.

Blood. 1999 Oct 15;94(8):2575-82.

PubMed [citation]

PMID:: 10515860

FAS gene mutation in a case of autoimmune lymphoproliferative syndrome type IA with accumulation of gammadelta+ T cells.

van den Berg A, Tamminga R, de Jong D, Maggio E, Kamps W, Poppema S.

Am J Surg Pathol. 2003 Apr;27(4):546-53.

PubMed [citation]

PMID:: 12657942

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001232048.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ile259 amino acid residue in FAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10515860). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 FAS protein function. ClinVar contains an entry for this variant (Variation ID: 860668). This variant is also known as Ile243Thr. This missense change has been observed in individual(s) with autoimmune lymphoproliferative syndrome (ALPS) (PMID: 12657942). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 259 of the FAS protein (p.Ile259Thr).

#	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 Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV004037578.1

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

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

Last Updated: Sep 29, 2024

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