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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:
1

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001232048Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Mar 10, 2023)
germlineclinical testing

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

SCV004037578Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenicmaternalclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedmaternalyes1not providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
11not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Sep 29, 2024