rs149391489

chrX-101401803-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4 BP6 BS2

The NM_000169.3(GLA):c.376A>G(p.Ser126Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00055 in 1,207,539 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 221 hemizygotes in GnomAD. In-silico tool predicts a benign 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. S126I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., 10 hem., cov: 23)
  • Exomes 𝑓: 0.00057 (0 hom. 211 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:14
• Conservation: PhyloP100: 2.56

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_benign. Variant got -4 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, 8 uncertain in NM_000169.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.36750877).
• BP6: Variant X-101401803-T-C is Benign according to our data. Variant chrX-101401803-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163547.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=11, Uncertain_significance=2, Benign=2}. Variant chrX-101401803-T-C is described in Lovd as [Pathogenic]. Variant chrX-101401803-T-C is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.376A>G	p.Ser126Gly	missense_variant	3/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.300+6346T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.376A>G	p.Ser126Gly	missense_variant	3/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 45 AN: 112278 Hom.: 0 Cov.: 23 AF XY: 0.000291 AC XY: 10 AN XY: 34416

Gnomad AFR AF: 0.0000648

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

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: 0.000769

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000327 AC: 60 AN: 183376 Hom.: 0 AF XY: 0.000324 AC XY: 22 AN XY: 67822

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000684

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000565 AC: 619 AN: 1095261 Hom.: 0 Cov.: 29 AF XY: 0.000585 AC XY: 211 AN XY: 360735

Gnomad4 AFR exome AF: 0.0000759

Gnomad4 AMR exome AF: 0.000142

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000740

Gnomad4 FIN exome AF: 0.000123

Gnomad4 NFE exome AF: 0.000697

Gnomad4 OTH exome AF: 0.000370

GnomAD4 genome AF: 0.000401 AC: 45 AN: 112278 Hom.: 0 Cov.: 23 AF XY: 0.000291 AC XY: 10 AN XY: 34416

Gnomad4 AFR AF: 0.0000648

Gnomad4 AMR AF: 0.000189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000769

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000763 Hom.: 28

Bravo AF: 0.000314

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000892 AC: 6

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.00115

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fabry disease Uncertain:2 Benign:7

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 29, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Ser126Gly variant in GLA has been reported in 3 individuals with Fabry disease, segregated with disease in these 3 affected relatives from one family (PMID: 22905681), and has also been identified in 0.074% (69/92714) of European (non-Finnish) chromosomes, including 24 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs149391489). This variant has also been reported in ClinVar as likely benign by the Laboratory for Molecular Medicine (Partners Healthcare), GeneDx, and Ambry Genetics and as a VUS by Division of Genomic Diagnostics (The Children's Hospital of Philadelphia) and Invitae (Variation ID: 163547). In vitro functional studies provide some evidence that the p.Ser126Gly variant may not impact protein function (PMID: 23935525, 11889412, 28646478). 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. In summary, while the clinical significance of the p.Ser126Gly variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_supporting, BS3_supporting, PP1 (Richards 2015). -
Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of Fabry disease (MIM#301500) (gnomAD v2.1.1 - 25 hemizygotes) (SB) 0805 - This variant has strong previous evidence of being benign in unrelated individuals. This variant has previously been reported as benign, likely benign and as a variant of uncertain significance (ClinVar). While this variant has also been reported in patients, population frequency supports this variant being benign (PMIDs:29132836; 31860127; 23935525; 33036343; 20360539). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 25, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 12, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2020	This variant is associated with the following publications: (PMID: 11889412, 29132836, 23935525, 24582695, 23219219, 26520229, 26652600, 20360539, 23306324, 23307880, 22905681, 25596309, 25382311, 28646478, 28283366, 28340804, 26990548, 29487688, 27657681, 31860127, 30477121) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	GLA: BS2 -
Uncertain significance, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 29, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 06, 2017	The p.Ser126Gly variant in GLA has been reported in a 12-year-old male with Fabr y disease, 1 adult female with stroke who had normal alpha-galactosidase levels, 1 female with unspecified clinical information, 1 female toddler with LVNC and arthrogryposis, 1 male toddler with neonatal onset DCM, and 2 adult females with HCM (Branton 2012, De Brabander 2013, Pasqualim 2014, LMM data). It has also be en identified in 0.07% (66/90653) of European chromosomes, including 23 hemizygo tes, in the gnomAD database (http://gnomad.broadinstitute.org; dbSNP rs149391489 ). Functional studies indicate that the p.Ser126Gly variant may reduce GLA enzym e function by 50%, but the clinical threshold and impact are not well characteri zed (Lukas 2013). A predictive model developed to determine the pathogenicity of variants in the GLA gene suggests that the p.Ser126Gly variant may not be damag ing (Riera 2015), though this information is not predictive enough to rule out p athogenicity. In summary, while the clinical significance of the p.Ser126Gly var iant is not conclusive, given the population frequency, presence of hemizygotes, inconsistency in phenotype in cases, and residual enzyme activity in functional studies, this variant is likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 30, 2021	Variant summary: GLA c.376A>G (p.Ser126Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 183376 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GLA causing Fabry Disease (0.00033 vs 0.005), allowing no conclusion about variant significance. c.376A>G has been identified in the literature without strong evidence for pathogenicity (e.g. Branton_2002, Colon_2017, Reisin_2018). At least one family study showed lack of co-segregation of the variant with the disease (DeBrabander_2013, Reisin_2018). In addition, a functional study found that GLA enzyme activity was reduced by ~50% in vitro, but also found that the lyso-Gb3 biomarker that is typically increased in Fabry patients was at normal levels in patient samples with the variant (Lukas_2013). Another in vitro enzyme activity study showed that the variant retained 83% of WT activity levels (Benjamin_2016). A recent study however, showed no significant reduction in enzymatic activity (Oommen_2019). Thirteen other ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=9) or uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 17, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
CardioboostCm	Benign	0.082
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Pathogenic	0.23
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Pathogenic	0.66
Sift	Benign	0.060	T;.
Sift4G	Benign	0.069	T;.
Polyphen		0.043	B;.
Vest4		0.68
MVP		1.0
MPC		0.70
ClinPred		0.050	T
GERP RS		3.5
Varity_R		0.75
gMVP		0.89

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: rs149391489; hg19: chrX-100656791;