NM_000157.4(GBA1):c.222_224del (p.Thr75del) AND Gaucher disease

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 16, 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:: RCV001775006.7

Allele description [Variation Report for NM_000157.4(GBA1):c.222_224del (p.Thr75del)]

NM_000157.4(GBA1):c.222_224del (p.Thr75del)

Genes:

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

Variant type:

Deletion

Cytogenetic location:

1q22

Genomic location:

Preferred name:

NM_000157.4(GBA1):c.222_224del (p.Thr75del)

Other names:

p.Thr75del

HGVS:

NC_000001.11:g.155239969_155239971del
NG_009783.1:g.9727_9729del
NG_042867.1:g.6431_6433del
NM_000157.4:c.222_224delMANE SELECT
NM_001005741.3:c.222_224del
NM_001005742.3:c.222_224del
NM_001171811.2:c.-40_-38del
NM_001171812.2:c.222_224del
NP_000148.2:p.Thr75del
NP_001005741.1:p.Thr75del
NP_001005742.1:p.Thr75del
NP_001165283.1:p.Thr75del
NC_000001.10:g.155209760_155209762del
NC_000001.10:g.155209760_155209762delGTA
NC_000001.11:g.155239969_155239971delGTA
NM_000157.4:c.222_224del
NM_001005741.2:c.222_224del
NM_001005741.2:c.222_224delTAC

Protein change:

T75del

Links:

dbSNP: rs761621516

NCBI 1000 Genomes Browser:

rs761621516

Molecular consequence:

NM_001171811.2:c.-40_-38del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000157.4:c.222_224del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001005741.3:c.222_224del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001005742.3:c.222_224del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001171812.2:c.222_224del - inframe_deletion - [Sequence Ontology: SO:0001822]

Observations:

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
SCV002011813	GeneID Lab - Advanced Molecular Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 8, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10796875, 19394250, 16293621, 25741868
SCV002086484	Natera, Inc.	no assertion criteria provided	Pathogenic (Oct 26, 2020)	germline	clinical testing
SCV003800841	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 16, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16293621, 10796875, 19394250, 15352589, 26792850 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002011813

GeneID Lab - Advanced Molecular Diagnostics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 8, 2019)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002086484

Natera, Inc.

no assertion criteria provided

Pathogenic
(Oct 26, 2020)

germline

clinical testing

SCV003800841

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 16, 2023)

germline

clinical testing

PubMed (5)
[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
African American	germline	no	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

Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations.

Liou B, Kazimierczuk A, Zhang M, Scott CR, Hegde RS, Grabowski GA.

J Biol Chem. 2006 Feb 17;281(7):4242-53. Epub 2005 Nov 17.

PubMed [citation]

PMID:: 16293621

See all PubMed Citations (6)

Details of each submission

From GeneID Lab - Advanced Molecular Diagnostics, SCV002011813.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	African American	1	not provided	not provided	clinical testing	PubMed (4)

Description

This variant results in an in-frame deletion, described as p.Thr75del. This finding has been described among non-Jewish patients with type 1 Gaucher disease (PMID: 10796875) and in affected patients from black South Africans population (PMID: 19394250). Aditionally experimental evidence suggest that the function of the protein harboring this substitution is impaired (PMID: 16293621). Based on these findings and the limited literature regarding this substitution we consider it as a "Pathogenic variant”.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		1	not provided	not provided	not provided

From Natera, Inc., SCV002086484.1

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003800841.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: GBA c.222_224delTAC (p.Thr75del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 5.2e-05 in 251342 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GBA causing Gaucher Disease (5.2e-05 vs 0.005), allowing no conclusion about variant significance. c.222_224delTAC has been reported in the literature in multiple individuals affected with Gaucher Disease (e.g., Koprivica_2000, Heitner_2004, Arndt_2009). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, suggesting the variant reduces enzymatic activity (e.g., Liou_2006, Arndt_2009). The most pronounced variant effect results in 35% of normal catalytic activity (Liou_2006), and in some compound heterozygous patient leukocytes, enzymatic activity was reported to range from 0% to 50% of normal activity (Arndt_2009). Seven ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic (n=6) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as 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 8, 2024

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