NM_000169.3:c.540G>C

Variant names:

• chrX-101401639-C-G
• rs869312145
• NM_000169.3:c.540G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS1_Moderate PM1 PM2 PP2 PP3 PP5

The NM_000169.3(GLA):​c.540G>C​(p.Leu180Phe) variant causes a missense change involving the alteration of a non-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. L180W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.26
• Publications: 0 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 9 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 25 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.78
• PP5: Variant X-101401639-C-G is Pathogenic according to our data. Variant chrX-101401639-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1747366.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.540G>C	p.Leu180Phe	missense_variant	Exon 3 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.540G>C	p.Leu180Phe	missense_variant	Exon 3 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+6182C>G		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Apr 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L180F variant (also known as c.540G>C), located in coding exon 3 of the GLA gene, results from a G to C substitution at nucleotide position 540. The leucine at codon 180 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in association with Fabry diease (Trimarchi H et al. J Transl Med, 2016 10;14:289; Rosa Neto NS et al. Mol Genet Metab Rep, 2020 Mar;22:100547; Balendran S et al. Clin Genet, 2020 04;97:655-660). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
CardioboostCm	Uncertain	0.62
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.81	D;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.3	M;.
PhyloP100		3.3
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.7	N;.
REVEL	Pathogenic	0.66
Sift	Benign	0.042	D;.
Sift4G	Benign	0.070	T;.
Polyphen		0.84	P;.
Vest4		0.80
MutPred		0.48		Gain of catalytic residue at L180 (P = 0.0479);.;
MVP		0.99
MPC		1.7
ClinPred		0.79	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.95
Mutation Taster		=35/65	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: rs869312145; hg19: chrX-100656627;