NM_000169.3:c.1088G>A

Variant names:

• chrX-101398011-C-T
• rs111422676
• NM_000169.3:c.1088G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 17P and 5B. PS3 PM1 PM5 PP2 PP5_Very_Strong BS1_Supporting BS2

The NM_000169.3(GLA):​c.1088G>A​(p.Arg363His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000257 in 1,207,965 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000695730: "In vitro enyzme activity assay showed this variant led to moderate decrease of enzyme activity."; SCV001422922: "In vitro functional studies provide some evidence that the p.Arg363His variant may slightly impact protein function (PMID:21598360, 23935525, 19387866)."; SCV001588429: Experimental studies have shown that this missense change affects GLA function (PMID:19387866, 21598360).; SCV001712060: "In vitro enzyme studies depict a moderate effect on enzyme activity which leads to an attenuated/atypical/late-onset phenotype (Lukas et al, 2013; Riera et al, 2015)."; SCV002053129: Functional studies have shown the mutant protein to exhibit significantly reduced GLA enzyme activity in vitro, with a greater than 70% decrease compared to wild type (PMID:21598360, 23935525).; SCV005426137: Biochemical testing in patient lymphoblasts showed reduced enzyme activity of 12% to 24% of normal activity (PMID:19387866, 21598360, respectively).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R363C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.000016 (0 hom. 9 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:2
• Conservation: PhyloP100: -0.0720
• Publications: 45 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 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000695730: "In vitro enyzme activity assay showed this variant led to moderate decrease of enzyme activity."; SCV001422922: "In vitro functional studies provide some evidence that the p.Arg363His variant may slightly impact protein function (PMID: 21598360, 23935525, 19387866)."; SCV001588429: Experimental studies have shown that this missense change affects GLA function (PMID: 19387866, 21598360).; SCV001712060: "In vitro enzyme studies depict a moderate effect on enzyme activity which leads to an attenuated/atypical/late-onset phenotype (Lukas et al, 2013; Riera et al, 2015)."; SCV002053129: Functional studies have shown the mutant protein to exhibit significantly reduced GLA enzyme activity in vitro, with a greater than 70% decrease compared to wild type (PMID: 21598360, 23935525).; SCV005426137: Biochemical testing in patient lymphoblasts showed reduced enzyme activity of 12% to 24% of normal activity (PMID: 19387866, 21598360, respectively).
• PM1: In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_000169.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101398012-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 198401.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.
• PP5: Variant X-101398011-C-T is Pathogenic according to our data. Variant chrX-101398011-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 222141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000125 (14/111964) while in subpopulation AMR AF = 0.00133 (14/10556). AF 95% confidence interval is 0.000802. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 9 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.1088G>A	p.Arg363His	missense	Exon 7 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.1211G>A	p.Arg404His	missense	Exon 8 of 8	NP_001393676.1	A0A3B3IUC4
	RPL36A-HNRNPH2	NM_001199973.2		c.300+2554C>T		intron	N/A	NP_001186902.2	H7BZ11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.1088G>A	p.Arg363His	missense	Exon 7 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+2554C>T		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.1211G>A	p.Arg404His	missense	Exon 8 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 14 AN: 111964 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00133

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000545 AC: 10 AN: 183364 AF XY: 0.0000885

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000155 AC: 17 AN: 1096001 Hom.: 0 Cov.: 30 AF XY: 0.0000249 AC XY: 9 AN XY: 361377

African (AFR) AF: 0.00 AC: 0 AN: 26360

American (AMR) AF: 0.0000852 AC: 3 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.000222 AC: 12 AN: 54092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4122

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840094

Other (OTH) AF: 0.00 AC: 0 AN: 46021

GnomAD4 genome AF: 0.000125 AC: 14 AN: 111964 Hom.: 0 Cov.: 23 AF XY: 0.000264 AC XY: 9 AN XY: 34152

African (AFR) AF: 0.00 AC: 0 AN: 30753

American (AMR) AF: 0.00133 AC: 14 AN: 10556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00 AC: 0 AN: 2733

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6061

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53222

Other (OTH) AF: 0.00 AC: 0 AN: 1504

Alfa AF: 0.0000831 Hom.: 1

Bravo AF: 0.000121

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	1	-	Fabry disease (14)
2	1	-	not provided (3)
1	-	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
CardioboostCm	Benign	0.023
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	12
DANN	Benign	0.75
DEOGEN2	Uncertain	0.67	D
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Pathogenic	2.0	D
MutationAssessor	Benign	1.9	L
PhyloP100		-0.072
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.44
Sift	Benign	0.47	T
Sift4G	Benign	0.51	T
Polyphen		0.41	B
Vest4		0.64
MutPred		0.86		Loss of sheet (P = 0.0817)
MVP		0.98
MPC		0.90
ClinPred		0.019	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.79
Mutation Taster		=56/44	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: rs111422676; hg19: chrX-100652999;