NM_000157.4(GBA):c.896T>C (p.Ile299Thr) AND Gaucher disease

Clinical significance:Likely pathogenic (Last evaluated: Jan 14, 2020)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000157.4(GBA):c.896T>C (p.Ile299Thr)]

NM_000157.4(GBA):c.896T>C (p.Ile299Thr)

LOC106627981:GBA recombination region [Gene]
GBA:glucosylceramidase beta [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000157.4(GBA):c.896T>C (p.Ile299Thr)
  • NC_000001.11:g.155237444A>G
  • NG_009783.1:g.12254T>C
  • NG_042867.1:g.3906A>G
  • NM_000157.4:c.896T>CMANE SELECT
  • NM_001005741.3:c.896T>C
  • NM_001005742.3:c.896T>C
  • NM_001171811.2:c.635T>C
  • NM_001171812.2:c.749T>C
  • NP_000148.2:p.Ile299Thr
  • NP_001005741.1:p.Ile299Thr
  • NP_001005742.1:p.Ile299Thr
  • NP_001165282.1:p.Ile212Thr
  • NP_001165283.1:p.Ile250Thr
  • NC_000001.10:g.155207235A>G
  • NM_001005741.2(GBA):c.896T>C
  • p.Ile299Thr
Protein change:
dbSNP: rs794727908
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000157.4:c.896T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001005741.3:c.896T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001005742.3:c.896T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001171811.2:c.635T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001171812.2:c.749T>C - missense variant - [Sequence Ontology: SO:0001583]


Gaucher disease
Acute cerebral Gaucher disease; Cerebroside lipidosis syndrome; Gaucher splenomegaly; See all synonyms [MedGen]
MONDO: MONDO:0018150; MedGen: C0017205

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV001422532Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedLikely pathogenic
(Jan 14, 2020)

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration



Perinatal lethal phenotype with generalized ichthyosis in a type 2 Gaucher disease patient with the [L444P;E326K]/P182L genotype: effect of the E326K change in neonatal and classic forms of the disease.

Chabás A, Gort L, Díaz-Font A, Montfort M, Santamaría R, Cidrás M, Grinberg D, Vilageliu L.

Blood Cells Mol Dis. 2005 Sep-Oct;35(2):253-8.

PubMed [citation]

Four Gaucher disease type II patients with three novel mutations: a single centre experience from Turkey.

Bulut FD, Kör D, Şeker-Yılmaz B, Hergüner Ö, Ceylaner S, Özkınay F, Kılavuz S, Önenli-Mungan N.

Metab Brain Dis. 2018 Aug;33(4):1223-1227. doi: 10.1007/s11011-018-0236-0. Epub 2018 Apr 14.

PubMed [citation]
See all PubMed Citations (3)

Details of each submission

From Broad Institute Rare Disease Group, Broad Institute, SCV001422532.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (3)


The p.Ile299Thr variant in GBA has been reported in 3 individuals with Gaucher disease and has been identified in 0.009% (3/34592) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs794727908). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 198757) as likely pathogenic by EGL Genetic Diagnostics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in one affected homozygote and in combination with reported pathogenic variants in 2 individuals with Gaucher disease increases the likelihood that the p.Ile299Thr variant is pathogenic (VariationID: 4288, 4290; PMID: 29656334, 15967693, 29423829). The phenotype of an individual homozygous for this variant is highly specific for Gaucher disease based on very low beta-glucosidase levels, massive hepatosplenomegaly, and neurological abnormalities consistent with disease (PMID: 29656334). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PP3, PP4 (Richards 2015).

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

Last Updated: Oct 7, 2021

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