rs869312159

Positions:

• chrX-101398401-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000169.3(GLA):​c.968C>G​(p.Pro323Arg) variant causes a missense change. 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6 O:1
• Conservation: PhyloP100: 3.67

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3	c.968C>G	p.Pro323Arg	missense_variant	6/7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.968C>G	p.Pro323Arg	missense_variant	6/7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+2944G>C		intron_variant		4		ENSP00000386655.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2021	This sequence change replaces proline with arginine at codon 323 of the GLA protein (p.Pro323Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of GLA-related conditions (PMID: 26415523). ClinVar contains an entry for this variant (Variation ID: 217406). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GLA function (PMID: 26415523). 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. -
Uncertain significance, 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	Jun 26, 2023	This missense variant replaces proline with arginine at codon 323 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 03, 2024	This missense variant replaces proline with arginine at codon 323 of the GLA protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. A functional study has shown that this variant leads to 63% residual alpha-galactosidase A (GLA) enzyme activity in transfected cells (PMID: 26415523). This variant has been reported in one individual suspected to be affected with Fabry disease (PMID: 26415523). This variant has not been identified 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 24, 2024

Variant summary: GLA c.968C>G (p.Pro323Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183503 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.968C>G has been reported in the literature in at-least one individual with clinical features of GLA-related condition (example: Lukas_2016) . These report(s) do not provide unequivocal conclusions about association of the variant with Fabry Disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity (Lukas_2016). The following publication has been ascertained in the context of this evaluation (PMID: 26415523). ClinVar contains an entry for this variant (Variation ID: 217406). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The p.P323R variant (also known as c.968C>G), located in coding exon 6 of the GLA gene, results from a C to G substitution at nucleotide position 968. The proline at codon 323 is replaced by arginine, an amino acid with dissimilar properties. In an assay testing GLA function, this variant showed a functionally indeterminant result (Lukas J et al. Hum Mutat, 2016 Jan;37:43-51). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

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	Benign	0.077
CardioboostCm	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;T
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.0	D;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.021	D;.
Sift4G	Uncertain	0.030	D;.
Polyphen		0.30	B;.
Vest4		0.82
MutPred		0.48		Loss of ubiquitination at K326 (P = 0.0456);.;
MVP		0.89
MPC		0.80
ClinPred		0.94	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.99

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: rs869312159; hg19: chrX-100653389;