NM_000157.4:c.680A>G

Variant names:

• chr1-155238215-T-C
• rs364897
• NM_000157.4:c.680A>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 17P and 1B. PS3 PM1 PM5 PP2 PP5_Very_Strong BP4

The NM_000157.4(GBA1):​c.680A>G​(p.Asn227Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,612,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000697592: "While the E326K variant does not have a significant effect on enzyme activity in these studies (and has not been observed in GD patients on its own), the addition of the variant of interest resulted in greater effects on activity (completely inactive in one study, 25% residual activity in a second study). PMID:24896178"" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N227R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 3.36
• Publications: 58 publications found

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]

GBA1 Gene-Disease associations (from GenCC):

• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Gaucher disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• Gaucher disease perinatal lethal

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, G2P
• late-onset Parkinson disease

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Gaucher disease type I

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• Gaucher disease type II

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Gaucher disease type III

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000697592: "While the E326K variant does not have a significant effect on enzyme activity in these studies (and has not been observed in GD patients on its own), the addition of the variant of interest resulted in greater effects on activity (completely inactive in one study, 25% residual activity in a second study). PMID:24896178"; SCV001422959: "In vitro functional studies provide some evidence that the p.Asn227Ser variant may slightly impact protein function either alone or in cis with another pathogenic variant." PMID:20004867, 26743617, 27865684, 30497978, 15146461, 24022302; SCV000960920: Experimental studies have shown that this missense change affects GBA function (PMID: 15146461, 20004867, 24022302).; SCV004009880: PS3:Supporting; SCV007107386: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV005849037: Experimental studies have shown that this missense change affects GBA function (Tajima A, et al., 2010).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000157.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155238214-AT-CC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167132.
• 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 type I, Gaucher disease type III, Gaucher disease type II, Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome, Gaucher disease perinatal lethal, Gaucher disease, Parkinson disease.
• PP5: Variant 1-155238215-T-C is Pathogenic according to our data. Variant chr1-155238215-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.221823). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000157.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	NM_000157.4	MANE Select	c.680A>G	p.Asn227Ser	missense	Exon 6 of 11	NP_000148.2	P04062-1
	GBA1	NM_001005741.3		c.680A>G	p.Asn227Ser	missense	Exon 7 of 12	NP_001005741.1	P04062-1
	GBA1	NM_001005742.3		c.680A>G	p.Asn227Ser	missense	Exon 7 of 12	NP_001005742.1	P04062-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	ENST00000368373.8	TSL:1 MANE Select	c.680A>G	p.Asn227Ser	missense	Exon 6 of 11	ENSP00000357357.3	P04062-1
	GBA1	ENST00000327247.9	TSL:1	c.680A>G	p.Asn227Ser	missense	Exon 7 of 12	ENSP00000314508.5	P04062-1
	GBA1	ENST00000948997.1		c.746A>G	p.Asn249Ser	missense	Exon 8 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152108 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000716 AC: 18 AN: 251308 AF XY: 0.0000883

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000582 AC: 85 AN: 1460174 Hom.: 0 Cov.: 32 AF XY: 0.0000564 AC XY: 41 AN XY: 726484

African (AFR) AF: 0.000120 AC: 4 AN: 33396

American (AMR) AF: 0.0000671 AC: 3 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39682

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86194

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1110550

Other (OTH) AF: 0.0000497 AC: 3 AN: 60324

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152226 Hom.: 0 Cov.: 30 AF XY: 0.0000672 AC XY: 5 AN XY: 74420

African (AFR) AF: 0.000265 AC: 11 AN: 41552

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.0000432 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
2	-	-	Gaucher disease (3)
2	-	-	Gaucher disease type I (2)
2	-	-	Gaucher disease type II;C0268251:Gaucher disease type III;C0752347:Lewy body dementia;C1842704:Gaucher disease perinatal lethal;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I;C3160718:Parkinson disease, late-onset (2)
1	-	-	Gaucher disease type II (1)
1	-	-	Gaucher disease type II;C0268251:Gaucher disease type III;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I (1)
1	-	-	Gaucher disease type III (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	19
DANN	Benign	0.46
DEOGEN2	Pathogenic	0.97	D
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.6	L
PhyloP100		3.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.49
Sift	Benign	0.24	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.61
MVP		0.80
MPC		0.61
ClinPred		0.32	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.90
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs364897; hg19: chr1-155208006; COSMIC: COSV105891369; COSMIC: COSV105891369;