NM_000169.3:c.335G>A

Variant names:

• chrX-101403845-C-T
• rs372966991
• NM_000169.3:c.335G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 21P and 4B. PS3 PM1 PM5 PP2 PP3_Strong PP5_Very_Strong BS2

The NM_000169.3(GLA):​c.335G>A​(p.Arg112His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,210,198 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000695739: Multiple publications report experimental evidence indicating that the variant severely impacts the enzymatic activity of the protein, resulting in <10% of normal activity (Ishii_2007, Shimotori_2007, Lukas_2013).; SCV000913664: Functional studies in both cells derived from hemizygous carrier individuals and in heterologous transfected cell lines have shown that this variant causes a significant reduction in residual GLA activity (PMID:17555407, 18205205, 32023956).; SCV000949841: Experimental studies have shown that this missense change does not substantially affect GLA function (PMID:17555407, 21598360, 23935525).; SCV001365616: Functional studies demonstrate that this variant is associated with reduced enzyme activity in patient samples (Nishida 2014) and in a transfected cell line (Shin 2007).; SCV001423099: "In vitro functional studies provide some evidence that the p.Arg112His variant may slightly impact protein function (PMID:30386727, 27896103, 18205205, 23935525, 17532296, 17555407)."; SCV005426161: Functional studies in both cells derived from hemizygous carrier individuals and in heterologous transfected cell lines have shown that this variant causes a significant reduction in residual GLA activity (PMID:17555407, 18205205, 32023956).; SCV006335987: At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:32023956;21598360;30723321;23474038;27657681;18205205).; SCV001829624: Published functional studies demonstrate decreased alpha galactosidase activity compared to wildtype (Lukas et al., 2013; Ishii et al., 2007); SCV002606289: "In multiple assays testing GLA function, this variant showed functionally abnormal results (Ishii S et al. Biochem. J., 2007 Sep;406:285-95; Lukas J et al. PLoS Genet., 2013 Aug;9:e1003632; Saito S et al. PLoS ONE, 2013 Dec;8:e84267; Shimotori M et al. Hum. Mutat., 2008 Feb;29:331; Shin SH et al. Biochem. Biophys. Res. Commun., 2007 Jul;359:168-73)."". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R112S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000018 (0 hom. 8 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23
• Conservation: PhyloP100: 7.71
• Publications: 95 publications found

Genes affected

GLA (HGNC:4296): (galactosidase alpha) This gene encodes a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. This enzyme predominantly hydrolyzes ceramide trihexoside, and it can catalyze the hydrolysis of melibiose into galactose and glucose. A variety of mutations in this gene affect the synthesis, processing, and stability of this enzyme, which causes Fabry disease, a rare lysosomal storage disorder that results from a failure to catabolize alpha-D-galactosyl glycolipid moieties. [provided by RefSeq, Jul 2008]

RPL36A-HNRNPH2 (HGNC:48349): (RPL36A-HNRNPH2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ribosomal protein L36a and heterogeneous nuclear ribonucleoprotein H2 (H') genes on chromosome X. The read-through transcript produces a protein with similarity to the protein encoded by the upstream locus, ribosomal protein L36a. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jan 2011]

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000695739: Multiple publications report experimental evidence indicating that the variant severely impacts the enzymatic activity of the protein, resulting in <10% of normal activity (Ishii_2007, Shimotori_2007, Lukas_2013).; SCV000913664: Functional studies in both cells derived from hemizygous carrier individuals and in heterologous transfected cell lines have shown that this variant causes a significant reduction in residual GLA activity (PMID: 17555407, 18205205, 32023956).; SCV000949841: Experimental studies have shown that this missense change does not substantially affect GLA function (PMID: 17555407, 21598360, 23935525).; SCV001365616: Functional studies demonstrate that this variant is associated with reduced enzyme activity in patient samples (Nishida 2014) and in a transfected cell line (Shin 2007).; SCV001423099: "In vitro functional studies provide some evidence that the p.Arg112His variant may slightly impact protein function (PMID: 30386727, 27896103, 18205205, 23935525, 17532296, 17555407)."; SCV005426161: Functional studies in both cells derived from hemizygous carrier individuals and in heterologous transfected cell lines have shown that this variant causes a significant reduction in residual GLA activity (PMID: 17555407, 18205205, 32023956).; SCV006335987: At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:32023956;21598360;30723321;23474038;27657681;18205205).; SCV001829624: Published functional studies demonstrate decreased alpha galactosidase activity compared to wildtype (Lukas et al., 2013; Ishii et al., 2007); SCV002606289: "In multiple assays testing GLA function, this variant showed functionally abnormal results (Ishii S et al. Biochem. J., 2007 Sep;406:285-95; Lukas J et al. PLoS Genet., 2013 Aug;9:e1003632; Saito S et al. PLoS ONE, 2013 Dec;8:e84267; Shimotori M et al. Hum. Mutat., 2008 Feb;29:331; Shin SH et al. Biochem. Biophys. Res. Commun., 2007 Jul;359:168-73)."
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 20 uncertain in NM_000169.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101403846-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4081422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 218 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 1.8759 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Fabry disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant X-101403845-C-T is Pathogenic according to our data. Variant chrX-101403845-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 195028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 8 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000169.3. 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
	GLA	NM_000169.3	MANE Select	c.335G>A	p.Arg112His	missense	Exon 2 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.458G>A	p.Arg153His	missense	Exon 3 of 8	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.335G>A	p.Arg112His	missense	Exon 2 of 6	NP_001393677.1	A0A6Q8PHD1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.335G>A	p.Arg112His	missense	Exon 2 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.301-8091C>T		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.458G>A	p.Arg153His	missense	Exon 3 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112660 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000375

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183395 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000182 AC: 20 AN: 1097538 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 8 AN XY: 362900

African (AFR) AF: 0.00 AC: 0 AN: 26392

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.0000214 AC: 18 AN: 841481

Other (OTH) AF: 0.0000434 AC: 2 AN: 46074

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112660 Hom.: 0 Cov.: 23 AF XY: 0.0000287 AC XY: 1 AN XY: 34812

African (AFR) AF: 0.00 AC: 0 AN: 31017

American (AMR) AF: 0.00 AC: 0 AN: 10650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3606

South Asian (SAS) AF: 0.00 AC: 0 AN: 2782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6201

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53311

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000273

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
15	-	-	Fabry disease (15)
7	-	-	not provided (7)
1	-	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
CardioboostCm	Uncertain	0.74
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.89
MVP		1.0
MPC		2.0
ClinPred		0.96	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs372966991; hg19: chrX-100658833; COSMIC: COSV105870802; COSMIC: COSV105870802;