NM_000169.3:c.680G>A

Variant names:

• chrX-101398906-C-T
• rs104894840
• NM_000169.3:c.680G>A

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000169.3(GLA):​c.680G>A​(p.Arg227Gln) variant causes a missense change involving the alteration of a 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000695744: "In functional studies, the variant was found to have greatly reduced enzymatic activity (Lukas_2013, Morrone_2003, Wu_2011)."" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R227P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.84
• Publications: 60 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 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000695744: "In functional studies, the variant was found to have greatly reduced enzymatic activity (Lukas_2013, Morrone_2003, Wu_2011)."; SCV000834471: Experimental studies have shown that this missense change affects GLA function (PMID: 21598360, 23935525).; SCV004013711: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18698230, 19387866, 21598360, 23935525, 27657681).; SCV005426148: "In vitro functional studies using transfected HEK-293 cells as well as patient-derived cell lines have shown that this variant causes a significant reduction in GLA enzyme activity (PMID: 18698230, 21598360, 23935525, 32023956)."; SCV006061193: "In vitro functional studies using transfected HEK-293 cells as well as patient-derived cell lines have shown that this variant causes a significant reduction in GLA enzyme activity (PMID: 18698230, 21598360, 23935525, 32023956)."; SCV006336234: At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:32023956;21598360;23935525;27657681).; SCV000207829: Functional studies in HEK-293 cells found that p.(R227Q) is associated with 0% residual enzyme activity compared to wild-type. PMID:21598360, 23935525
• PM1: In a hotspot region, there are 34 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101398906-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 217394.Status of the report is criteria_provided_single_submitter, 1 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, 0.992
• PP5: Variant X-101398906-C-T is Pathogenic according to our data. Variant chrX-101398906-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.680G>A	p.Arg227Gln	missense	Exon 5 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.803G>A	p.Arg268Gln	missense	Exon 6 of 8	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.680G>A	p.Arg227Gln	missense	Exon 5 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.680G>A	p.Arg227Gln	missense	Exon 5 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+3449C>T		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.803G>A	p.Arg268Gln	missense	Exon 6 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Fabry disease (9)
4	-	-	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	5.0	H
PhyloP100		7.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.97		Loss of MoRF binding (P = 0.0795)
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.7
Varity_R		1.0
gMVP		1.0
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs104894840; hg19: chrX-100653894;