NM_000169.3(GLA):c.1087C>T (p.Arg363Cys) AND Fabry disease

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Jan 19, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001249019.18

Allele description [Variation Report for NM_000169.3(GLA):c.1087C>T (p.Arg363Cys)]

NM_000169.3(GLA):c.1087C>T (p.Arg363Cys)

Genes:

RPL36A-HNRNPH2:RPL36A-HNRNPH2 readthrough [Gene - HGNC]
GLA:galactosidase alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq22.1

Genomic location:

Preferred name:

NM_000169.3(GLA):c.1087C>T (p.Arg363Cys)

HGVS:

NC_000023.11:g.101398012G>A
NG_007119.1:g.14952C>T
NM_000169.3:c.1087C>TMANE SELECT
NM_001199973.2:c.300+2555G>A
NM_001199974.2:c.177+6190G>A
NM_001406747.1:c.1210C>T
NP_000160.1:p.Arg363Cys
NP_000160.1:p.Arg363Cys
NP_001393676.1:p.Arg404Cys
LRG_672t1:c.1087C>T
LRG_672:g.14952C>T
LRG_672p1:p.Arg363Cys
NC_000023.10:g.100653000G>A
NM_000169.2(GLA):c.1087C>T
NM_000169.2:c.1087C>T
NR_164783.1:n.1166C>T
NR_176252.1:n.1017C>T
NR_176253.1:n.1224C>T
p.Arg363Cys

Protein change:

R363C

Links:

dbSNP: rs797044776

NCBI 1000 Genomes Browser:

rs797044776

Molecular consequence:

NM_001199973.2:c.300+2555G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+6190G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.1087C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406747.1:c.1210C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.1166C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176252.1:n.1017C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176253.1:n.1224C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Fabry disease
Synonyms:: Angiokeratoma, diffuse; Anderson-Fabry disease; Hereditary dystopic lipidosis; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010526; MedGen: C0002986; Orphanet: 324; OMIM: 301500; Human Phenotype Ontology: HP:0001071

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001422923	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 22, 2020)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001430847	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	no assertion criteria provided	Likely pathogenic (Jun 27, 2019)	germline	research	PubMed (5) [See all records that cite these PMIDs] 12175777, 28615118, 28749998, 29661900, 19387866
SCV001554529	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jul 1, 2022)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 19387866, 21598360, 15924232, 12175777, 21138548, 22063097, 15003450, 27916943, 28749998, 31860127, 29437868, 32442237, 30103270, 28615118, 29661900, 25762495 Citation Link,
SCV001575313	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21598360, 11668641, 12175777, 26937405, 28302345, 28492532
SCV001736310	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 9, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002054374	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002807958	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 8, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The pharmacological chaperone 1-deoxygalactonojirimycin increases alpha-galactosidase A levels in Fabry patient cell lines.

Benjamin ER, Flanagan JJ, Schilling A, Chang HH, Agarwal L, Katz E, Wu X, Pine C, Wustman B, Desnick RJ, Lockhart DJ, Valenzano KJ.

J Inherit Metab Dis. 2009 Jun;32(3):424-40. doi: 10.1007/s10545-009-1077-0. Epub 2009 Apr 18.

PubMed [citation]

PMID:: 19387866

Fabry disease: correlation between structural changes in alpha-galactosidase, and clinical and biochemical phenotypes.

Matsuzawa F, Aikawa S, Doi H, Okumiya T, Sakuraba H.

Hum Genet. 2005 Aug;117(4):317-28. Epub 2005 May 28.

PubMed [citation]

PMID:: 15924232

See all PubMed Citations (21)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422923.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

The p.Arg363Cys variant in GLA has been reported in the literature in two males with classic Fabry, as well as in five individuals in ClinVar (PMID: 12175777, 21598360; ID:198401), and has been identified in 0.00244% (2/81841) of European (non-Finnish) chromosomes, including 1 hemizygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs797044776). 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. This variant has also been reported in ClinVar as pathogenic by EGL Genetic Diagnostics (VariationID:198401). In vitro functional studies provide some evidence that the p.Arg363Cys variant may slightly impact protein function (PMID: 21598360, 27744182, 19387866). 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 an individual hemizygous for this variant is highly specific for Fabry disease based on the classical phenotype that is consistent with disease (PMID: 12175777). One additional likely pathogenic variant, causing a different amino acid change at the same position, p.Arg363His, has been reported in association with disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 21598360, 28302345,12175777, 23935525, 26937405,11668641,25382311/Variation ID: 222141). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2_supporting, PS3_supporting, PS4_moderate, PP4, PM5_supporting (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, SCV001430847.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (5)

Description

GLA Arg353Cys has been previously identified in 5 Fabry patients (Phyu P, et al., 2018; Pettazzoni M, et al., 2017; Benjamin ER, et al., 2009; Shabbeer J, et al., 2002). We identified this variant in a patient presenting with left ventricular hypertrophy, subsequent clinical screening confirmed a diagnosis of Fabry disease. The variant is present at a low frequency in the Genome Aggregation Database (MAF= 0.000011 http://gnomad.broadinstitute.org/). In silico tools SIFT and PolyPhen-2 predict this variant to be benign, however MutationTaster predicts this variant to be "Disease causing". Interestingly another amino acid change at this position (Arg363His) has been classified as pathogenic. suggesting that an amino acid substitution at this site may not be tolerated. In summary, based on rarity in the general population, reports of this variant in affected individuals, and because Fabry disease is caused only by variants in the GLA gene, we classify GLA Arg353Cys as "likely pathogenic".

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001554529.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

Variant summary: GLA c.1087C>T (p.Arg363Cys) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 183376 control chromosomes (gnomAD). c.1087C>T has been reported in the literature in individuals affected with later onset or non-classic presentations of Fabry Disease (example, Balendran_2020, Mauhin_2020, Arends_2018) and as a variant causing classical Fabry disease (example, Shabbeer_2002, cited in Benjamin_2009). These data do not allow a firm conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function (example, Wu_2011, Benjamin_2009). The most pronounced variant effect results in <10% of normal activity. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 citing overlapping evidence utilized in the context of this evaluation. All submitters classified the variant as pathogenic (n=3)/likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001575313.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 363 of the GLA protein (p.Arg363Cys). This variant is present in population databases (rs797044776, gnomAD 0.002%). This missense change has been observed in individual(s) with features of Fabry disease (PMID: 12175777; Invitae). ClinVar contains an entry for this variant (Variation ID: 198401). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects GLA function (PMID: 21598360). This variant disrupts the p.Arg363 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11668641, 12175777, 26937405, 28302345). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV001736310.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant replaces arginine with cysteine at codon 363 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 7.5% residual GLA enzyme activity when expressed in HEK-293 cells (PMID: 21598360). This variant has been reported in individuals affected with Fabry disease (PMID: 12175777, 19387866, 28749998, 29661900, 32442237) and a female with left ventricular hypertrophy (PMID: 31987665). Cultured cells from an affected male showed 8% residual GLA enzyme activity (PMID: 19387866), and an affected female showed elevated lysoglobotriaosylceramide levels (PMID: 28749998). This variant has been reported in a newborn (PMID: 28615118) and in a 33-year-old asymptomatic female (PMID: 31117083). Both of them had reduced GLA enzyme activity. This variant has been identified in 2/183376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg363His, has been associated with Fabry disease (Clinvar variation ID: 222141), indicating that arginine at this position is important for the protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002054374.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002807958.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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