NM_000169.3(GLA):c.604T>C (p.Cys202Arg) AND Fabry disease

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 20, 2022
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:: RCV001039833.12

Allele description [Variation Report for NM_000169.3(GLA):c.604T>C (p.Cys202Arg)]

NM_000169.3(GLA):c.604T>C (p.Cys202Arg)

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.604T>C (p.Cys202Arg)

HGVS:

NC_000023.11:g.101400701A>G
NG_007119.1:g.12263T>C
NM_000169.3:c.604T>CMANE SELECT
NM_001199973.2:c.300+5244A>G
NM_001199974.2:c.177+8879A>G
NP_000160.1:p.Cys202Arg
NP_000160.1:p.Cys202Arg
LRG_672t1:c.604T>C
LRG_672:g.12263T>C
LRG_672p1:p.Cys202Arg
NC_000023.10:g.100655689A>G
NM_000169.2:c.604T>C
NR_164783.1:n.626T>C

Protein change:

C202R

Links:

dbSNP: rs1569303843

NCBI 1000 Genomes Browser:

rs1569303843

Molecular consequence:

NM_001199973.2:c.300+5244A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+8879A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.604T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.626T>C - 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
SCV001203382	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 20, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9100224, 19387866, 23935525, 31020198, 28492532
SCV002054813	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]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001203382

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 20, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002054813

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]

Help

Summary from all submissions

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

Citations

PubMed

Fabry disease: thirty-five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes.

Eng CM, Ashley GA, Burgert TS, Enriquez AL, D'Souza M, Desnick RJ.

Mol Med. 1997 Mar;3(3):174-82.

PubMed [citation]

PMID:: 9100224
PMCID:: PMC2230047

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

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001203382.6

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys202 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9100224, 19387866, 23935525). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 633244). This missense change has been observed in individual(s) with Fabry disease (PMID: 31020198). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 202 of the GLA protein (p.Cys202Arg).

#	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, SCV002054813.1

#	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

Last Updated: Jul 15, 2024

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