NM_000169.3:c.124A>C

Variant names:

• chrX-101407780-T-G
• rs797044613
• NM_000169.3:c.124A>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 17P and 4B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong BS2

The NM_000169.3(GLA):​c.124A>C​(p.Met42Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,209,691 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M42I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000036 (0 hom. 3 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.79
• Publications: 29 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 13 ACMG points.

• PM1: In a hotspot region, there are 53 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000169.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101407778-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 594121.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, 0.99
• PP5: Variant X-101407780-T-G is Pathogenic according to our data. Variant chrX-101407780-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 193056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.124A>C	p.Met42Leu	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.124A>C	p.Met42Leu	missense_variant	Exon 1 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.301-4156T>G		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112099 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097592 Hom.: 0 Cov.: 31 AF XY: 0.00000827 AC XY: 3 AN XY: 362950

African (AFR) AF: 0.00 AC: 0 AN: 26392

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19379

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54131

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 841534

Other (OTH) AF: 0.00 AC: 0 AN: 46075

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112099 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34261

African (AFR) AF: 0.00 AC: 0 AN: 30826

American (AMR) AF: 0.00 AC: 0 AN: 10653

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00 AC: 0 AN: 2703

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6123

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53147

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:5

Dec 18, 2019

Clinical Genomics Laboratory, Stanford Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Met42Leu variant in the GLA gene has been previously reported in two unrelated males with Fabry disease (Rosenthal et al., 2004; Shabbeer, Robinson & Desnick, 2005). Alpha-galactosidase A enzyme activity was tested and reported low in one of the published individuals. This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Wellestablished in vitro functional studies of p.Met42Leu variant strongly suggest a deleterious effect to the protein that is sufficient to be disease-causing (Benjamin et al., 2017; Oommen et al., 2019). Additionally, multiple different amino acid changes, p.Met42Ile, p.Met42Thr, and p.Met42Val, have been previously reported as disease-causing at this residue, which suggests another change at this residue, such as p.Met42Leu, may similarly disrupt protein function. The p.Met42Leu variant is located in a region where other pathogenic and likely pathogenic variants have been described without benign variation. Pathogenic and likely pathogenic variants have been described in this region and disrupt the function of GLA, resulting in reduced or absent alpha-galactosidase A enzyme activity. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Met42Leu variant as pathogenic for X-linked Fabry disease based on the information above. [ACMG evidence codes used: PS3; PM1; PM2; PM5; PP4] -

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with leucine at codon 42 of the GLA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. In vitro functional studies in transfected HEK-293 cells have shown that this variant causes a significant reduction in GLA activity (PMID: 27657681, 31036492). This variant has been reported in individuals affected with Fabry disease, including two with a renal variant of Fabry disease (PMID: 15492942, 15712228, 32802993; DOI:10.16966/2380-5498.124). Different variants affecting the same codon, p.Met42Val and p.Met42Thr, are considered to be disease-causing (ClinVar variation ID: 222174, 92541), suggesting that methionine at this position is important for GLA protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Sep 12, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with leucine at codon 42 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In vitro functional studies in transfected HEK-293 cells have shown that this variant causes a significant reduction in GLA activity (PMID: 27657681, 31036492). This variant has been reported in individuals affected with Fabry disease, including two with a renal variant of Fabry disease (PMID: 15492942, 15712228, 32802993; DOI:10.16966/2380-5498.124). Different variants affecting the same codon, p.Met42Val and p.Met42Thr, are considered to be disease-causing (ClinVar variation ID: 222174, 92541), suggesting that methionine at this position is important for GLA protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 42 of the GLA protein (p.Met42Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 15492942, 15712228; http//dx.doi.org/10.16966/2380-5498.124). ClinVar contains an entry for this variant (Variation ID: 193056). 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 have shown that this missense change affects GLA function (PMID: 27657681). This variant disrupts the p.Met42 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8875188, 12175777, 18205205, 23935525, 26415523, 27560961). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Jun 26, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 13, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10666480, 17391432, 25382311, 35653365, 30386727, 15712228, 27657681, 31036492, 15492942) -

Cardiovascular phenotype Pathogenic:1

Apr 24, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M42L variant (also known as c.124A>C), located in coding exon 1 of the GLA gene, results from an A to C substitution at nucleotide position 124. The methionine at codon 42 is replaced by leucine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with Fabry disease (Rosenthal D et al. Am J Kidney Dis, 2004 Nov;44:e85-9). This variant has also been reported in cardiomyopathy cohort (Stava TT et al. Eur J Prev Cardiol, 2022 Oct;29:1789-1799). Anther variant at the same codon, p.M42I (c.126G>A) has been identified in individual(s) with features consistent with Fabry disease (Pan X et al. PLoS One, 2016 Aug;11:e0161330). Functional studies suggest enzyme activity levels less than the wildtype; however, additional evidence is needed to confirm these findings (Benjamin ER et al. Genet Med, 2017 Apr;19:430-438; Oommen S et al. Mol Genet Metab, 2019 May;127:74-85). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
CardioboostCm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.95	D;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		7.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.010	D;.
Polyphen		0.98	D;.
Vest4		0.86
MutPred		0.95		Loss of methylation at R38 (P = 0.1822);Loss of methylation at R38 (P = 0.1822);
MVP		1.0
MPC		1.6
ClinPred		0.99	D
GERP RS		5.4
PromoterAI		0.060	Neutral
Varity_R		0.97
gMVP		0.99
Mutation Taster		=12/88	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

Other links and lift over

dbSNP: rs797044613; hg19: chrX-100662768;