NM_000169.3:c.926C>T

Variant names:

• chrX-101398443-G-A
• rs869312155
• NM_000169.3:c.926C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A309P) has been classified as Likely pathogenic.

• 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:6 O:1
• Conservation: PhyloP100: 1.04
• Publications: 3 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 25 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 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-101398444-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4087582.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.926C>T	p.Ala309Val	missense_variant	Exon 6 of 7	ENST00000218516.4	NP_000160.1

Ensembl

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

African (AFR) AF: 0.00 AC: 0 AN: 26363

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19376

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54091

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4111

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839963

Other (OTH) AF: 0.0000217 AC: 1 AN: 45999

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Uncertain:4

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Sep 15, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 309 of the GLA protein (p.Ala309Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Fabry disease (PMID: 26415523). ClinVar contains an entry for this variant (Variation ID: 217401). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GLA protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GLA function (PMID: 26415523). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 18, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

- 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;.
PhyloP100		1.0
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
Mutation Taster		=31/69	disease causing

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

Other links and lift over

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