NM_000157.4(GBA1):c.999+242C>A AND Gaucher disease type I

Germline classification:: Pathogenic (1 submission)
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:: RCV000999462.3

Allele description [Variation Report for NM_000157.4(GBA1):c.999+242C>A]

NM_000157.4(GBA1):c.999+242C>A

Genes:

LOC106627981:GBA recombination region [Gene]
GBA1:glucosylceramidase beta 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q22

Genomic location:

Preferred name:

NM_000157.4(GBA1):c.999+242C>A

HGVS:

NC_000001.11:g.155237099G>T
NG_009783.1:g.12599C>A
NG_042867.1:g.3561G>T
NM_000157.4:c.999+242C>AMANE SELECT
NM_001005741.3:c.999+242C>A
NM_001005742.3:c.999+242C>A
NM_001171811.2:c.738+242C>A
NM_001171812.2:c.852+242C>A
NC_000001.10:g.155206890G>T
c.999+242C>A

Links:

dbSNP: rs1571969643

NCBI 1000 Genomes Browser:

rs1571969643

Molecular consequence:

NM_000157.4:c.999+242C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001005741.3:c.999+242C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001005742.3:c.999+242C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001171811.2:c.738+242C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001171812.2:c.852+242C>A - intron variant - [Sequence Ontology: SO:0001627]

Functional consequence:

cryptic splice donor activation [Variation Ontology: 0374]

Observations:

Condition(s)

Name:: Gaucher disease type I (GD1)
Synonyms:: GBA DEFICIENCY; GD I; Gaucher's disease, type 1; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009265; MedGen: C1961835; Orphanet: 355; Orphanet: 77259; OMIM: 230800

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yn84b02.s1 Soares adult brain N2b5HB55Y Homo sapiens cDNA clone IMAGE:175083 3', mRNA sequence
gi|908458|gnl|dbEST|299654|gb|H3895

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000930452	Biochemical Genetics Department, Cyprus Institute of Neurology and Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 31943857

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000930452

Biochemical Genetics Department, Cyprus Institute of Neurology and Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
Greek-Cypriot	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

A novel mutation deep within intron 7 of the GBA gene causes Gaucher disease.

Malekkou A, Sevastou I, Mavrikiou G, Georgiou T, Vilageliu L, Moraitou M, Michelakakis H, Prokopiou C, Drousiotou A.

Mol Genet Genomic Med. 2020 Mar;8(3):e1090. doi: 10.1002/mgg3.1090. Epub 2020 Jan 14.

PubMed [citation]

PMID:: 31943857
PMCID:: PMC7057115

Details of each submission

From Biochemical Genetics Department, Cyprus Institute of Neurology and Genetics, SCV000930452.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Greek-Cypriot	1	not provided	not provided	clinical testing	PubMed (2)

Description

The g.12599C>A (c.999+242C>A) variant in the GBA gene was found in one Cypriot family with low glucocerebrosidase (GCase) enzyme activity. The proband was homozygous for this mutation. The mutation was also found in the heterozygous state in one of the parents (the other parent is not alive), one sister and four children of the proband, and was absent in controls. Proband's cDNA analysis revealed that this variant creates a new splice donor site leading to the insertion of the first 239 nucleotides of intron 7 in mRNA, resulting in a premature stop codon. In summary, g.7764C>A (c.999+242C>A) variant meets our criteria to be classified as pathogenic.

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

Last Updated: Jun 23, 2024

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