chr1-155235708-G-A

Variant names:

• chr1-155235708-G-A
• NM_000157.4:c.1361C>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000157.4(GBA1):​c.1361C>T​(p.Pro454Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P454R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.94

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

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000157.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155235708-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 4289.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 1-155235708-G-A is Pathogenic according to our data. Variant chr1-155235708-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1722541.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA1	NM_000157.4	c.1361C>T	p.Pro454Leu	missense_variant	Exon 9 of 11	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8	c.1361C>T	p.Pro454Leu	missense_variant	Exon 9 of 11	1	NM_000157.4	ENSP00000357357.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459180 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725558

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lewy body dementia Pathogenic:1

Oct 28, 2022

Research Unit of Clinical Medicine, Medical Research Center Oulu, University of Oulu

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

The variant replaces highly conserved proline at amino acid position 454 with leucine. Pathogenic variant p.Pro454Arg has been reported in the position causing Gaucher disease with another pathogenic variant in trans. The variant p.Pro454Leu has not been described in literature or in the databases. Pathogenicity prediction algorithm PredictSNP supported deleterious nature of the variant. The variant was found in two siblings with a severe disease with Lewy bodies and a family history of dominant inheritance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M;M;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-9.8	D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.97
MutPred		0.92		Gain of ubiquitination at K452 (P = 0.0758);Gain of ubiquitination at K452 (P = 0.0758);.;.;
MVP		0.97
MPC		1.8
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.98
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-155205499;