NM_000157.4(GBA1):c.222_224del (p.Thr75del) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jul 29, 2024
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:: RCV000796019.12

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000935509	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10796875, 19394250, 16293621, 28492532
SCV002018403	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 25, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002028208	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 29, 2024)	germline	clinical testing	Citation Link,
SCV004228232	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 9, 2022)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 10796875, 12587096, 16293621, 17059888, 19394250, 21704274, 30169122, 30548430, 32035846, 25741868

Help

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease.

Koprivica V, Stone DL, Park JK, Callahan M, Frisch A, Cohen IJ, Tayebi N, Sidransky E.

Am J Hum Genet. 2000 Jun;66(6):1777-86. Epub 2000 May 4.

PubMed [citation]

PMID:: 10796875
PMCID:: PMC1378059

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000935509.5

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

Description

This variant, c.222_224del, results in the deletion of 1 amino acid(s) of the GBA protein (p.Thr75del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs761621516, gnomAD 0.04%). This variant has been observed in individuals with Gaucher disease (PMID: 10796875, 19394250). This variant is also known as T36del. ClinVar contains an entry for this variant (Variation ID: 642539). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects GBA function (PMID: 16293621). For these reasons, this variant has been 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

From Revvity Omics, Revvity, SCV002018403.3

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

#	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 GeneDx, SCV002028208.4

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

Description

Published functional studies demonstrate a damaging effect with this variant resulting in deceased enzyme activity (PMID: 16293621); In-frame deletion of one amino acid in a non-repeat region; Also known as p.T36del using alternate nomenclature; This variant is associated with the following publications: (PMID: 10796875, 30548430, 29625052, 32035846, 36451132, 16293621, 19394250)

#	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		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV004228232.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (10)

Description

PP4, PM2, PM3_strong, PM4, PS3_moderate, PS4_moderate

#	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		1	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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