NM_000157.4(GBA1):c.776A>G (p.Tyr259Cys) AND Gaucher disease

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 8, 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:: RCV003331970.1

Allele description [Variation Report for NM_000157.4(GBA1):c.776A>G (p.Tyr259Cys)]

NM_000157.4(GBA1):c.776A>G (p.Tyr259Cys)

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.776A>G (p.Tyr259Cys)

HGVS:

NC_000001.11:g.155237564T>C
NG_009783.1:g.12134A>G
NG_042867.1:g.4026T>C
NM_000157.4:c.776A>GMANE SELECT
NM_001005741.3:c.776A>G
NM_001005742.3:c.776A>G
NM_001171811.2:c.515A>G
NM_001171812.2:c.629A>G
NP_000148.2:p.Tyr259Cys
NP_001005741.1:p.Tyr259Cys
NP_001005742.1:p.Tyr259Cys
NP_001165282.1:p.Tyr172Cys
NP_001165283.1:p.Tyr210Cys
NC_000001.10:g.155207355T>C
NM_001005741.2:c.776A>G

Protein change:

Y172C

Molecular consequence:

NM_000157.4:c.776A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001005741.3:c.776A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001005742.3:c.776A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001171811.2:c.515A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001171812.2:c.629A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004038412	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Aug 8, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 17059888, 30764785, 34649574, 34867278, 29685539, 35262230, 32613234 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004038412

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Aug 8, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

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

Citations

PubMed

Detection of 12 new mutations in Gaucher disease Brazilian patients.

Rozenberg R, Fox DC, Sobreira E, Pereira LV.

Blood Cells Mol Dis. 2006 Nov-Dec;37(3):204-9. Epub 2006 Oct 23.

PubMed [citation]

PMID:: 17059888

Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation.

Sheth J, Bhavsar R, Mistri M, Pancholi D, Bavdekar A, Dalal A, Ranganath P, Girisha KM, Shukla A, Phadke S, Puri R, Panigrahi I, Kaur A, Muranjan M, Goyal M, Ramadevi R, Shah R, Nampoothiri S, Danda S, Datar C, Kapoor S, Bhatwadekar S, et al.

BMC Med Genet. 2019 Feb 14;20(1):31. doi: 10.1186/s12881-019-0759-1.

PubMed [citation]

PMID:: 30764785
PMCID:: PMC6376752

See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004038412.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: GBA c.776A>G (p.Tyr259Cys, aka Y220C) results in a non-conservative amino acid change located in the TIM-barrel domain (IPR033453) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250282 control chromosomes (gnomAD). c.776A>G has been reported in the literature in multiple compound heterozygous individuals, and in at least one homozygous patient, affected with Gaucher Disease (e.g. Rozenberg_2006, Kang_2018, D'Amore_2021, Sheth_2019), in most cases the diagnosis was confirmed by deficient GBA activity. In addition, the variant has been also reported in heterozygous state in patients affected with Parkinson disease (e.g. Zhao_2020, Zhao_2021, Straniero_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17059888, 29685539, 34649574, 30764785, 32613234, 34867278, 35262230). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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: Oct 7, 2023

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