rs398123202

Variant names:

• chrX-101407772-C-A
• rs398123202
• NM_000169.3:c.132G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-101407772-C-A
• chrX-101407772-C-G
• chrX-101407772-C-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1_Moderate PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000169.3(GLA):​c.132G>T​(p.Trp44Cys) 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W44G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.68
• Publications: 6 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 14 ACMG points.

• PS1: Transcript NM_000169.3 (GLA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 60 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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-101407774-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4087662.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, 0.993
• PP5: Variant X-101407772-C-A is Pathogenic according to our data. Variant chrX-101407772-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 495693.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.132G>T	p.Trp44Cys	missense_variant	Exon 1 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.132G>T	p.Trp44Cys	missense_variant	Exon 1 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.301-4164C>A		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fabry disease Pathogenic:1 Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GLA c.132G>T (p.Trp44Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183425 control chromosomes (gnomAD). c.132G>T has been reported in the literature in multiple individuals affected with Fabry Disease (e.g. Wang_2005, Kobayashi_2019, Najafian_2020, Dutra-Clarke_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16215932, 20629180, 25382311, 26712400, 33437642, 34745889, 29631605, 30988410, 32127409). ClinVar contains an entry for this variant (Variation ID: 495693). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Uncertain:1

Aug 22, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	1.0	D;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	4.6	H;.
PhyloP100		7.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-11	D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;.
Vest4		1.0
MutPred		0.90		Gain of phosphorylation at T41 (P = 0.1234);Gain of phosphorylation at T41 (P = 0.1234);
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		-0.0015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
gMVP		1.0
Mutation Taster		=0/100	disease causing

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: rs398123202; hg19: chrX-100662760;