rs375661583

Variant names:

• chrX-101397915-C-G
• rs375661583
• NM_000169.3:c.1184G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 7P and 4B. PM1 PM5 PP2 PP3_Moderate BS2

The NM_000169.3(GLA):​c.1184G>C​(p.Gly395Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 1,208,708 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G395R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000011 (0 hom. 2 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 5.42
• Publications: 16 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000169.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101397915-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4087655.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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.1184G>C	p.Gly395Ala	missense_variant	Exon 7 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.1184G>C	p.Gly395Ala	missense_variant	Exon 7 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+2458C>G		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes AF: 0.0000355 AC: 4 AN: 112547 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: 0.0000751

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183463 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 12 AN: 1096161 Hom.: 0 Cov.: 30 AF XY: 0.00000553 AC XY: 2 AN XY: 361545

African (AFR) AF: 0.00 AC: 0 AN: 26366

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19372

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54103

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.0000131 AC: 11 AN: 840231

Other (OTH) AF: 0.0000217 AC: 1 AN: 46016

GnomAD4 genome AF: 0.0000355 AC: 4 AN: 112547 Hom.: 0 Cov.: 23 AF XY: 0.0000288 AC XY: 1 AN XY: 34743

African (AFR) AF: 0.00 AC: 0 AN: 30954

American (AMR) AF: 0.00 AC: 0 AN: 10636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3609

South Asian (SAS) AF: 0.00 AC: 0 AN: 2763

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6201

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

European-Non Finnish (NFE) AF: 0.0000751 AC: 4 AN: 53295

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Uncertain:5

Dec 13, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with alanine at codon 395 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). Functional studies have shown that this variant leads to a 13-24% level of residual GLA enzyme activity when expressed in HEK293 cells (PMID: 21598360). This variant has been reported in a few individuals and families affected with Fabry disease (PMID: 26880903, 27825144, 29487688, 30477121, 35971858, 36709535), in an individual suspected of having Fabry disease (PMID: 21896204), and in five asymptomatic relatives of the affected carriers (PMID: 29487688, 32806660). This variant has been identified in 2/183463 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. -

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with alanine at codon 395 of the GLA protein (p.Gly395Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs375661583, ExAC 0.002%). This missense change has been observed in individual(s) with clinical features of Fabry disease (PMID: 21896204, 27825144, 29487688, 30477121). ClinVar contains an entry for this variant (Variation ID: 405511). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects GLA function (PMID: 23935525). 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. -

Apr 01, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with alanine at codon 395 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. Functional studies have shown that this variant leads to a 13-24% level of residual GLA enzyme activity when expressed in HEK293 cells (PMID: 21598360). This variant has been reported in a few individuals and families affected with Fabry disease (PMID: 26880903, 27825144, 29487688, 30477121, 35971858, 36709535), in an individual suspected to be affected with Fabry disease (PMID: 21896204), and in five asymptomatic relatives of the affected carrier individuals (PMID: 29487688, 32806660). This variant has been identified in 2/183463 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. -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Gly395Ala variant in GLA has been reported in up to 10 Southern Italian families with Fabry disease (PMID: 21896204, 29487688, 27825144), and has been identified in 0.0024% (2/81904) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs375661583). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry Disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar as a VUS by Invitae (ID: 405511). In vitro functional studies provide some evidence that the p.Gly395Ala variant may slightly impact protein function through decreased enzyme function (PMID: 23935525). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual hemizygous for this variant is highly specific for Fabry disease based on the classic phenotype that is consistent with disease (PMID: 21896204, 29487688, 27825144). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP4, PM2_supporting, PP3, PS4_supporting, PS3_supporting (Richards 2015). -

Oct 20, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

Feb 27, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
CardioboostCm	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.64
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.8	M;.
PhyloP100		5.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.3	D;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.029	D;.
Sift4G	Uncertain	0.042	D;.
Polyphen		1.0	D;.
Vest4		0.87
MVP		0.99
MPC		1.8
ClinPred		0.96	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.94
Mutation Taster		=1/99	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: rs375661583; hg19: chrX-100652903;