rs104894834

Variant names:

• chrX-101403846-G-A
• rs104894834
• NM_000169.3:c.334C>T
• GLA p.Arg112Cys

Your query was ambiguous. Multiple possible variants found:

• chrX-101403846-G-A
• chrX-101403846-G-T

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.334C>T​(p.Arg112Cys) variant causes a missense change. 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: "SCV000568187: Published functional studies functional studies have demonstrated that R112C results in reduced enzyme activity compared to the wild-type (Ishii et al., 1992" and additional evidence is available in ClinVar. 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: not found (cov: 24)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 4.28
• Publications: 90 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: SCV000568187: Published functional studies functional studies have demonstrated that R112C results in reduced enzyme activity compared to the wild-type (Ishii et al., 1992; Yasuda et al., 2003; Lukas et al., 2013);; SCV000917444: "experimental evidence evaluating an impact on protein function (Shin 2008, Pieroni 2003)."; SCV001390681: Experimental studies have shown that this missense change affects GLA function (PMID: 1315715, 11137837, 14635108, 19287194, 21598360, 23935525, 26456105).; SCV004829276: "Well-established functional studies suggest that this variant results in a deleterious effect to the protein that is sufficient to be disease-causing." PMID: 14635108, 19287194, 23935525; SCV006335985: At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:32023956;21598360;23935525;27657681).; SCV002607129: Functional studies indicated that cells expressing this alteration demonstrated absent alpha-galactosidase enzyme activity and accumulation of elevated levels of Lyso-Gb3 (Yasuda M et al. Hum Mutat, 2003 Dec;22:486-92; Park JY et al. Exp Mol Med, 2009 Jan;41:1-7; Wu X et al. Hum Mutat, 2011 Aug;32:965-77; Lukas J et al. PLoS Genet, 2013 Aug;9:e1003632).
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 21 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-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, 0.98
• PP5: Variant X-101403846-G-A is Pathogenic according to our data. Variant chrX-101403846-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 92550.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.334C>T	p.Arg112Cys	missense	Exon 2 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.457C>T	p.Arg153Cys	missense	Exon 3 of 8	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.334C>T	p.Arg112Cys	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.334C>T	p.Arg112Cys	missense	Exon 2 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.301-8090G>A		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.457C>T	p.Arg153Cys	missense	Exon 3 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Fabry disease (7)
5	-	-	not provided (5)
1	-	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
CardioboostCm	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.76
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		4.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.99
Mutation Taster		=5/95	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs104894834;

hg19: chrX-100658834;

COSMIC: COSV105103411;

COSMIC: COSV105103411;