NM_000157.4(GBA1):c.1448T>G (p.Leu483Arg) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 8, 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:: RCV000414719.15

Allele description

NM_000157.4(GBA1):c.1448T>G (p.Leu483Arg)

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.1448T>G (p.Leu483Arg)

HGVS:

NC_000001.11:g.155235252A>C
NG_009783.1:g.14446T>G
NG_042867.1:g.1714A>C
NM_000157.4:c.1448T>GMANE SELECT
NM_001005741.2(GBA):c.1448T>G
NM_001005741.3:c.1448T>G
NM_001005742.3:c.1448T>G
NM_001171811.2:c.1187T>G
NM_001171812.2:c.1301T>G
NP_000148.2:p.Leu483Arg
NP_001005741.1:p.Leu483Arg
NP_001005742.1:p.Leu483Arg
NP_001165282.1:p.Leu396Arg
NP_001165283.1:p.Leu434Arg
NC_000001.10:g.155205043A>C
NM_000157.3:c.1448T>G
NM_001005741.2(GBA):c.1448T>G
NM_001005741.2:c.1448T>G

Protein change:

L396R

Links:

dbSNP: rs421016

NCBI 1000 Genomes Browser:

rs421016

Molecular consequence:

NM_000157.4:c.1448T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001005741.3:c.1448T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001005742.3:c.1448T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001171811.2:c.1187T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001171812.2:c.1301T>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000491299	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Feb 1, 2022)	germline	clinical testing	Citation Link,
SCV000700297	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Sep 18, 2013)	germline	clinical testing	Citation Link,
SCV001208546	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 7981693, 27825739, 8294487, 15146461, 24020503, 26096741, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000491299

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Feb 1, 2022)

germline

clinical testing

Citation Link,

SCV000700297

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Pathogenic
(Sep 18, 2013)

germline

clinical testing

Citation Link,

SCV001208546

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 8, 2024)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	7	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

New Gaucher disease mutations in exon 10: a novel L444R mutation produces a new NciI site the same as L444P.

Uchiyama A, Tomatsu S, Kondo N, Suzuki Y, Shimozawa N, Fukuda S, Sukegawa K, Taki N, Inamori H, Orii T.

Hum Mol Genet. 1994 Jul;3(7):1183-4. No abstract available.

PubMed [citation]

PMID:: 7981693

Use of a multiplex ligation-dependent probe amplification method for the detection of deletions/duplications in the GBA1 gene in Gaucher disease patients.

Basgalupp SP, Siebert M, Vairo FPE, Chami AM, Pinto LLC, Carvalho GDS, Schwartz IVD.

Blood Cells Mol Dis. 2018 Feb;68:17-20. doi: 10.1016/j.bcmd.2016.10.013. Epub 2016 Oct 20.

PubMed [citation]

PMID:: 27825739

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000491299.4

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(L444R); This variant is associated with the following publications: (PMID: 24278166, 10649495, 26043810, 28003644, 7981693, 27535533, RiboldiGM2019[review], 31912918, 27717005, 27825739)

#	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 Eurofins Ntd Llc (ga), SCV000700297.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	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		7	not provided	not provided	not provided

From Invitae, SCV001208546.5

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 483 of the GBA protein (p.Leu483Arg). This variant is present in population databases (rs421016, gnomAD 0.006%). This missense change has been observed in individual(s) with Gaucher disease (PMID: 7981693, 27825739). This variant is also known as L444R. ClinVar contains an entry for this variant (Variation ID: 93449). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GBA protein function with a positive predictive value of 80%. This variant disrupts the p.Leu483 amino acid residue in GBA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8294487, 15146461, 24020503, 26096741). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Last Updated: Jun 23, 2024

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