NM_000169.3:c.724A>G

Variant names:

• chrX-101398862-T-C
• rs397515873
• NM_000169.3:c.724A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP2 BP4

The NM_000169.3(GLA):​c.724A>G​(p.Ile242Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,204,523 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 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. I242F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:7 O:1
• Conservation: PhyloP100: 2.27
• Publications: 7 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 6 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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-101398861-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 4087482.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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34772268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.724A>G	p.Ile242Val	missense_variant	Exon 5 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.724A>G	p.Ile242Val	missense_variant	Exon 5 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+3405T>C		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112339 Hom.: 0 Cov.: 23

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: 0.00000366 AC: 4 AN: 1092184 Hom.: 0 Cov.: 30 AF XY: 0.00000280 AC XY: 1 AN XY: 357634

African (AFR) AF: 0.00 AC: 0 AN: 26287

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19353

East Asian (EAS) AF: 0.00 AC: 0 AN: 30188

South Asian (SAS) AF: 0.00 AC: 0 AN: 54013

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4100

European-Non Finnish (NFE) AF: 0.00000478 AC: 4 AN: 836645

Other (OTH) AF: 0.00 AC: 0 AN: 45863

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112339 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34485

African (AFR) AF: 0.00 AC: 0 AN: 30907

American (AMR) AF: 0.00 AC: 0 AN: 10563

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3614

South Asian (SAS) AF: 0.00 AC: 0 AN: 2718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6151

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

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53296

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:1 Uncertain:5

Jul 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 242 of the GLA protein (p.Ile242Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GLA-related conditions. ClinVar contains an entry for this variant (Variation ID: 217396). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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). This variant disrupts the p.Ile242 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 9105656, 23935525, 30386727, 33016649), which suggests that this may be a clinically significant amino acid residue. 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. -

Feb 03, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces isoleucine with valine at codon 242 of the GLA protein. Computational prediction suggests that this variant may not impact protein structure and function. Several in vitro functional studies have shown that this variant is associated with a greater than 80% residual GLA enzyme activity (PMID: 26415523, 31649303). This variant has been reported in several individuals referred for Fabry testing with mild or non-classical phenotype (PMID: 26415523, 27356758, 31649303, 32198894). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 19, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile242Val variant in GLA has been reported in 1 individual referred for Fabry testing with mildly elevated Globotriaosylceramide (Lukas 2016), was absent from large population studies. It has also been reported by other clinical laboratories in ClinVar (Variation ID: 217396). In vitro functional studies provide some evidence that the p.Ile242Val variant may mildly impact protein function (Lukas 2016). Isoleucine (Ile) at position 242 is not conserved in mammals or evolutionarily distant species and 6 species (including 4 mammals) carry a valine (Val) at this position, supporting that this change may be tolerated. Additional computational prediction tools suggest that the p.Ile242Val variant may not impact the protein. In summary, while the clinical significance of the p.Ile242Val variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PM2; PS3_Supporting; BP4. -

Feb 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jan 05, 2017

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. The I242V variant has been reported in one patient referred for Fabry disease testing who had slightly elevated levels of Globotriaosylceramide (Lukas et al., 2016). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the I242V 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 several species. In silico analysis predicts this variant likely does not alter the protein structure/function. Finally, while missense variants affecting the same residue (I242N, I242F) have been reported in the Human Gene Mutation Database in association with Fabry disease (Stenson et al., 2014), the pathogencity of these variants has not been definitively determined. -

Cardiovascular phenotype Uncertain:1

Sep 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I242V variant (also known as c.724A>G), located in coding exon 5 of the GLA gene, results from an A to G substitution at nucleotide position 724. The isoleucine at codon 242 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in Fabry disease cohorts (Lenders M et al. Orphanet J Rare Dis, 2016 May;11:54; Xiao K et al. Sci Rep, 2019 Oct;9:15277). An in vitro assay showed this alteration has >50% enzyme activity compared to wild-type (Lukas J et al. Hum Mutat, 2016 Jan;37:43-51). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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: yes

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
CardioboostCm	Benign	0.023
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Uncertain	0.78	D;.
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Pathogenic	1.4	D
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		2.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.80	N;.
REVEL	Uncertain	0.36
Sift	Benign	0.090	T;.
Sift4G	Benign	0.12	T;.
Polyphen		0.017	B;.
Vest4		0.72
MutPred		0.51		Loss of catalytic residue at I242 (P = 0.078);.;
MVP		0.93
MPC		0.60
ClinPred		0.28	T
GERP RS		3.6
Varity_R		0.45
gMVP		0.89
Mutation Taster		=26/74	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: rs397515873; hg19: chrX-100653850;