chrX-101398443-G-A

Position:

• chrX-101398443-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000169.3(GLA):​c.926C>T​(p.Ala309Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,095,839 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 O:1
• Conservation: PhyloP100: 1.04

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]

GLA (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3	c.926C>T	p.Ala309Val	missense_variant	6/7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.926C>T	p.Ala309Val	missense_variant	6/7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+2986G>A		intron_variant		4		ENSP00000386655.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1095839 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 361259

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 15, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, no assertion criteria provided	research	Albrecht-Kossel-Institute, Medical University Rostock	Jan 01, 2014	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2016	A variant of uncertain significance has been identified in the GLA gene. While the A309V variant has not been published in association with cardiomyopathy, it has been reported in a patient undergoing testing for Fabry disease (Lukas et al., 2016). However, functional studies show that cells expressing this variant have approximately 50% enzyme activity when compared to wild type cells which is consistent with a mild form of Fabry disease (Lukas et al., 2016). The A309V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species and where Valine is the wild type in one non-mammalian species. In silico analysis suggests this variant likely does not alter the protein structure/function. Nevertheless, the A309V was not observed in the Exome Aggregation Consortium.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -

Migalastat response Other:1

drug response, no assertion criteria provided

research

Albrecht-Kossel-Institute, Medical University Rostock

Jan 01, 2014

- Pharmacological Chaperone response: no

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
CardioboostCm	Benign	0.082
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.92	D;.
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.2	N;.
REVEL	Uncertain	0.30
Sift	Benign	0.24	T;.
Sift4G	Benign	0.26	T;.
Polyphen		0.46	P;.
Vest4		0.24
MutPred		0.44		Loss of helix (P = 0.0558);.;
MVP		0.93
MPC		0.74
ClinPred		0.31	T
GERP RS		3.0
Varity_R		0.66
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869312155; hg19: chrX-100653431; COSMIC: COSV54508720; COSMIC: COSV54508720;