rs1555986305

Positions:

• chrX-101403915-G-A
• chrX-101403915-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000169.3(GLA):​c.265C>T​(p.Leu89Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L89P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 0.767

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a disulfide_bond (size 42) in uniprot entity AGAL_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3	c.265C>T	p.Leu89Phe	missense_variant	2/7	ENST00000218516.4	NP_000160.1
RPL36A-HNRNPH2	NM_001199973.2	c.301-8021G>A		intron_variant			NP_001186902.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.265C>T	p.Leu89Phe	missense_variant	2/7	1	NM_000169.3	ENSP00000218516	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fabry disease Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 27, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 453314). This missense change has been observed in individual(s) with classic Fabry disease and reduced alpha-galactosidase enzyme activity (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 89 of the GLA protein (p.Leu89Phe). -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 07, 2016	Variant summary: The GLA c.265C>T (p.Leu89Phe) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 87749 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 21, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
CardioboostCm	Uncertain	0.76
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.81	L;.
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.3	N;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.0040	D;.
Polyphen		0.99	D;.
Vest4		0.31
MutPred		0.48		Gain of sheet (P = 0.1451);.;
MVP		0.97
MPC		1.7
ClinPred		0.81	D
GERP RS		1.8
Varity_R		0.80
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555986305; hg19: chrX-100658903;