NM_000169.3(GLA):c.170A>C (p.Gln57Pro) AND Fabry disease

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 5, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001563580.3

Allele description [Variation Report for NM_000169.3(GLA):c.170A>C (p.Gln57Pro)]

NM_000169.3(GLA):c.170A>C (p.Gln57Pro)

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.170A>C (p.Gln57Pro)

HGVS:

NC_000023.11:g.101407734T>G
NG_007119.1:g.5230A>C
NG_016327.1:g.4532T>G
NM_000169.3:c.170A>CMANE SELECT
NM_001199973.2:c.301-4202T>G
NM_001199974.2:c.178-4202T>G
NM_001406747.1:c.170A>C
NM_001406748.1:c.170A>C
NM_001406749.1:c.170A>C
NP_000160.1:p.Gln57Pro
NP_000160.1:p.Gln57Pro
NP_001393676.1:p.Gln57Pro
NP_001393677.1:p.Gln57Pro
NP_001393678.1:p.Gln57Pro
LRG_672t1:c.170A>C
LRG_672:g.5230A>C
LRG_672p1:p.Gln57Pro
NC_000023.10:g.100662722T>G
NM_000169.2:c.170A>C
NR_164783.1:n.192A>C
NR_176252.1:n.192A>C
NR_176253.1:n.192A>C

Protein change:

Q57P

Links:

dbSNP: rs869312260

NCBI 1000 Genomes Browser:

rs869312260

Molecular consequence:

NM_001199973.2:c.301-4202T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.178-4202T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.170A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406747.1:c.170A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406748.1:c.170A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406749.1:c.170A>C - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.192A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176252.1:n.192A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176253.1:n.192A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

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
SCV001786552	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 5, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19387866, 21598360, 25741868, 32901917

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001786552

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 5, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	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

A pharmacogenetic approach to identify mutant forms of α-galactosidase A that respond to a pharmacological chaperone for Fabry disease.

Wu X, Katz E, Della Valle MC, Mascioli K, Flanagan JJ, Castelli JP, Schiffmann R, Boudes P, Lockhart DJ, Valenzano KJ, Benjamin ER.

Hum Mutat. 2011 Aug;32(8):965-77. doi: 10.1002/humu.21530. Epub 2011 Jul 12.

PubMed [citation]

PMID:: 21598360
PMCID:: PMC3170878

See all PubMed Citations (4)

Details of each submission

From 3billion, SCV001786552.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

The heterozygous variant (NM_000169.2:c.170A>C) is absent from gnomAD v2.1.1. It is located in an exonic hotspot where pathogenic variants are frequently reported. Different pathogenic amino acid change [c.164A>T/c.171G>A (p.Asp55Val/Gln57Leu)] has been reported at the same codon (PMID 19387866 and 21598360). Missense variant of GLA gene is a common mechanism associated with Fabry disease. Patient's phenotype including stroke and proteinuria is considered as compatible with Fabry disease. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Sep 16, 2024

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