chr1-155235217-C-G

Variant names:

• chr1-155235217-C-G
• rs368060
• NM_000157.4:c.1483G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP2

The NM_000157.4(GBA1):​c.1483G>C​(p.Ala495Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000581 in 1,612,176 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A495G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., cov: 25)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:1
• Conservation: PhyloP100: 1.14

Genes affected

GBA1 (HGNC:4177): (glucosylceramidase beta 1) This gene encodes a lysosomal membrane protein that cleaves the beta-glucosidic linkage of glycosylceramide, an intermediate in glycolipid metabolism. Mutations in this gene cause Gaucher disease, a lysosomal storage disease characterized by an accumulation of glucocerebrosides. A related pseudogene is approximately 12 kb downstream of this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000157.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.1739 (below the threshold of 3.09). Trascript score misZ: 2.2879 (below the threshold of 3.09). GenCC associations: The gene is linked to late-onset Parkinson disease, Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome, Parkinson disease, Gaucher disease type III, Gaucher disease perinatal lethal, Gaucher disease, Gaucher disease type I, Gaucher disease type II.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA1	NM_000157.4	c.1483G>C	p.Ala495Pro	missense_variant	Exon 10 of 11	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8	c.1483G>C	p.Ala495Pro	missense_variant	Exon 10 of 11	1	NM_000157.4	ENSP00000357357.3

Frequencies

GnomAD3 genomes AF: 0.000787 AC: 119 AN: 151116 Hom.: 1 Cov.: 25

Gnomad AFR AF: 0.000948

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00285

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000980

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000340

Gnomad OTH AF: 0.00146

GnomAD2 exomes AF: 0.000139 AC: 35 AN: 251138 AF XY: 0.000118

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000556 AC: 813 AN: 1460942 Hom.: 0 Cov.: 31 AF XY: 0.000581 AC XY: 422 AN XY: 726720

Gnomad4 AFR exome AF: 0.000867 AC: 29 AN: 33460

Gnomad4 AMR exome AF: 0.00114 AC: 51 AN: 44676

Gnomad4 ASJ exome AF: 0.0000383 AC: 1 AN: 26130

Gnomad4 EAS exome AF: 0.00174 AC: 69 AN: 39634

Gnomad4 SAS exome AF: 0.00124 AC: 107 AN: 86052

Gnomad4 FIN exome AF: 0.0000749 AC: 4 AN: 53418

Gnomad4 NFE exome AF: 0.000462 AC: 513 AN: 1111470

Gnomad4 Remaining exome AF: 0.000646 AC: 39 AN: 60348

GnomAD4 genome AF: 0.000813 AC: 123 AN: 151234 Hom.: 1 Cov.: 25 AF XY: 0.000812 AC XY: 60 AN XY: 73894

Gnomad4 AFR AF: 0.000921 AC: 0.000921167 AN: 0.000921167

Gnomad4 AMR AF: 0.00317 AC: 0.00317334 AN: 0.00317334

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000983 AC: 0.000982704 AN: 0.000982704

Gnomad4 SAS AF: 0.00105 AC: 0.00105086 AN: 0.00105086

Gnomad4 FIN AF: 0.0000948 AC: 0.0000947508 AN: 0.0000947508

Gnomad4 NFE AF: 0.000340 AC: 0.000339644 AN: 0.000339644

Gnomad4 OTH AF: 0.00144 AC: 0.00144231 AN: 0.00144231

Alfa AF: 0.000869 Hom.: 0

ExAC AF: 0.000115 AC: 14

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Pathogenic:1 Uncertain:1 Benign:1

Jul 24, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 24, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.[L483P;A495P;V499V] pathogenic mutation (also known as c.[1448T>C;1483G>C;1497G>C]), located in coding exon 10 of the GBA gene, results from a T to C substitution at nucleotide position 1448, a G to C substitution at nucleotide position 1483, and a G to C substitution at nucleotide position 1497. This complex allele, also referred to as recNciI and L444P;A456P;V460V, has been reported in multiple cases of Gaucher disease, either in homozygous state or in trans with another GBA pathogenic mutation. It has been suggested that the complex allele results from gene recombination between GBA and its pseudogene (Zimran A et al. J. Clin. Invest., 1990 Jan;85:219-22; Latham T et al. Am. J. Hum. Genet., 1990 Jul;47:79-86; Horowitz M et al. Am. J. Hum. Genet., 1993 Oct;53:921-30; Strasberg PM et al. Biochem. Med. Metab. Biol., 1994 Oct;53:16-21; Sidransky E et al. J. Med. Genet., 1996 Feb;33:132-6; Tayebi N et al. Am. J. Hum. Genet., 2003 Mar;72:519-34; Saranjam H et al. Eur. J. Hum. Genet., 2013 Jan;21:115-7). In addition, functional studies showed that the complex allele greatly reduces enzyme activity (Grace ME et al. J. Biol. Chem., 1994 Jan;269:2283-91; Pasmanik-Chor M et al. Hum. Mol. Genet., 1997 Jun;6:887-95). Based on the supporting evidence, this complex allele is interpreted as a disease-causing mutation. -

Aug 20, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GBA1 c.1483G>C (p.Ala495Pro) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, beta sandwich domain (IPR033452) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 1612176 control chromosomes, predominantly at a frequency of 0.0017 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in GBA1 causing Gaucher Disease (0.00058 vs 0.005), allowing no conclusion about variant significance. c.1483G>C has been reported in the literature as part of the frequently encountered GBA complex alleles, RecTL or Rec NciI in individuals affected with Gaucher Disease and GBA-associated phenotypes of Parkinson Disease (example, Latham_1990, Grace_1994, Zimran_1994, Lau_1999, Stone_2000, Wittman_2012, Jesus_2016, Bhutada_2018, Kang_2018, Marchi_2020, Petrucci_2020). Rec TL and Rec NCiI are complex recombination alleles that carry two or more disease causing mutations due to gene conversion events between the GBA and the pseudo-GBA (GBAP) genes. To our knowledge, this variant has never been reported in isolation as a homozygous or compound heterozygous genotype in individuals with Gaugher Disease. These report(s) do not provide unequivocal conclusions about association of the variant with Gaucher Disease. At least one publication reports in-vitro experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Grace_1994). The following publications have been ascertained in the context of this evaluation (PMID: 29854527, 8294487, 28030538, 29934114, 2349952, 10369158, 32031266, 32658388, 38647370, 10685993, 23430949, 8160756). ClinVar contains an entry for this variant (Variation ID: 93450). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Pathogenic:1 Uncertain:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GBA1: PM2, PM3, PP1, PP4 -

Sep 29, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.85	D;D;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.59	.;T;T;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.3	M;M;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Pathogenic	0.67
Sift	Benign	0.20	T;T;T;T
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.037	B;B;.;.
Vest4		0.58
MVP		0.93
MPC		1.6
ClinPred		0.013	T
GERP RS		2.2
Varity_R		0.68
gMVP		0.95
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs368060; hg19: chr1-155205008; COSMIC: COSV105891350;