X-101397903-C-G

Position:

• chrX-101397903-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000169.3(GLA):​c.1196G>C​(p.Trp399Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,205,957 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000044 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000034 (0 hom. 18 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:14 O:1
• Conservation: PhyloP100: 3.44

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]

GLA (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11818567).
• BS2: High Hemizygotes in GnomAdExome4 at 18 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3	c.1196G>C	p.Trp399Ser	missense_variant	7/7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.1196G>C	p.Trp399Ser	missense_variant	7/7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+2446C>G		intron_variant		4		ENSP00000386655.4

Frequencies

GnomAD3 genomes AF: 0.0000444 AC: 5 AN: 112729 Hom.: 0 Cov.: 23 AF XY: 0.0000287 AC XY: 1 AN XY: 34899

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: 0.00180

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000818 AC: 15 AN: 183471 Hom.: 0 AF XY: 0.000103 AC XY: 7 AN XY: 67905

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000786

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000338 AC: 37 AN: 1093175 Hom.: 0 Cov.: 30 AF XY: 0.0000502 AC XY: 18 AN XY: 358725

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000611

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000871

GnomAD4 genome AF: 0.0000443 AC: 5 AN: 112782 Hom.: 0 Cov.: 23 AF XY: 0.0000286 AC XY: 1 AN XY: 34962

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00181

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:1 Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 17, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 19, 2022	This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 399 of the GLA protein (p.Trp399Ser). This variant is present in population databases (rs782449839, gnomAD 0.08%). This missense change has been observed in individual(s) with late-onset Fabry disease (PMID: 26415523, 28253518, 33495303). ClinVar contains an entry for this variant (Variation ID: 217414). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
Likely pathogenic, no assertion criteria provided	research	Albrecht-Kossel-Institute, Medical University Rostock	Jan 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 30, 2023	This missense variant replaces tryptophan with serine at codon 399 of the GLA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant leads to 53% residual alpha-galactosidase A (GLA) enzyme activity in transfected cells (PMID: 26415523). This variant has been reported in four individuals affected with Fabry disease (PMID: 26415523, 28253518, 29794742). This variant has also been identified in 15/183471 chromosomes (15/19080 South Asian chromosomes) 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. -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Trp399Ser variant in GLA has been reported in at least 3 individuals with Fabry disease (PMID: 26415523,28253518, 29794742), and has been identified in 0.08% (15/19080) of South Asian chromosomes, including 7 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs782449839). This variant has also been reported in ClinVar as likely pathogenic by Albrecht-Kossel-Institute (Medical University Rostock) and a VUS by Invitae (ID: 217414). In vitro functional studies provide some evidence that the p.Trp399Se variant may not impact protein function (PMID: 26415523). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of individuals hemizygous for this variant is highly specific for Fabry disease based on the classical phenotype which is consistent with disease (PMID: 26415523, 28253518, 28728877). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BS1, PP4, PS4_supporting, BS3_supporting (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 27, 2021	This missense variant replaces tryptophan with serine at codon 399 of the GLA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant leads to 53% residual alpha-galactosidase A (GLA) enzyme activity in transfected cells (PMID: 26415523). This variant has been reported in four individuals affected with Fabry disease (PMID: 26415523, 28253518, 29794742). This variant has also been identified in 15/183471 chromosomes (15/19080 South Asian chromosomes) 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 23, 2020	- -

not provided Uncertain:4

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 01, 2017	p.Trp399Ser (c.1196G>C) in GLA, Exon 7, (NM_000169.2; chrX-100652891-C-G) SCICD Classification: variant of uncertain significance, probably benign based on the allele frequency. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Case data (not including our patient): Reported with Fabry. Per the lab report "This variant has been reported in individuals affected with late-onset Fabry disease (PMID: 26415523,)." Population data: Highest MAF in South Asian population: 0.07835% in gnomAD exomes (ExAC) -
Uncertain significance, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 22, 2021

Variant summary: GLA c.1196G>C (p.Trp399Ser) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-05 in 183471 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GLA causing Fabry Disease (8.2e-05 vs 0.005), allowing no conclusion about variant significance. c.1196G>C has been reported in the literature in individuals affected with Later-onset Fabry Disease and slightly elevated levels of lyso-Gb3 and in one homozygous female with particularly severe clinical manifestations including cardiomyopathy and beginning kidney failure (Nowak_2017, Nowak_2018, Oder_2018). The later-onset male patient cohort has also been subsequently cited by others. These report(s) do not provide unequivocal conclusions about association of the variant with classic Fabry Disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50% of normal alpha-Galactosidase A enzyme activity in-vitro (example, Lukas_2016). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Jan 20, 2022

ACMG categories: PM1,PM2,PP3 -

Hypertrophic cardiomyopathy 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

May 18, 2020

- -

Migalastat response Other:1

drug response, no assertion criteria provided

research

Albrecht-Kossel-Institute, Medical University Rostock

Jan 01, 2014

- Pharmacological Chaperone response: no

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
CardioboostCm	Benign	0.049
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Benign	0.79
DEOGEN2	Uncertain	0.57	D;.
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.63	T;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.070	N;.
REVEL	Uncertain	0.55
Sift	Benign	0.54	T;.
Sift4G	Benign	0.82	T;.
Polyphen		0.57	P;.
Vest4		0.71
MutPred		0.56		Gain of disorder (P = 5e-04);.;
MVP		0.93
MPC		1.2
ClinPred		0.12	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.94

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: rs782449839; hg19: chrX-100652891;