1-155236254-G-T

Position:

• chr1-155236254-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000157.4(GBA1):​c.1215C>A​(p.Ser405Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S405N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.73

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 14 ACMG points.

• PS1: Transcript NM_000157.4 (GBA1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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 chr1-155236255-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1799687.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 1-155236254-G-T is Pathogenic according to our data. Variant chr1-155236254-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2503945.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4	c.1215C>A	p.Ser405Arg	missense_variant	8/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.1215C>A	p.Ser405Arg	missense_variant	8/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gaucher disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 26, 2023

Variant summary: GBA c.1215C>A (p.Ser405Arg) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251312 control chromosomes. c.1215C>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Gaucher Disease (example, Malini_2014, Miano_2020, Costa_2020). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (Malini_2014). The most pronounced variant effect results in a near complete loss of GBA activity in transiently transfected cells. The following publications have been ascertained in the context of this evaluation (PMID: 31816052, 30461613, 24022302, 24904648, 32702516). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;M;.;.
MutationTaster	Benign	0.75	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.88
MutPred		0.67		Gain of MoRF binding (P = 0.007);Gain of MoRF binding (P = 0.007);.;.;
MVP		0.96
MPC		1.6
ClinPred		0.96	D
GERP RS		2.6
Varity_R		0.91
gMVP		0.98

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: rs75528494; hg19: chr1-155206045;