NM_000169.3(GLA):c.118C>T (p.Pro40Ser) AND Fabry disease

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 8, 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:: RCV000011466.15

Allele description [Variation Report for NM_000169.3(GLA):c.118C>T (p.Pro40Ser)]

NM_000169.3(GLA):c.118C>T (p.Pro40Ser)

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.118C>T (p.Pro40Ser)

HGVS:

NC_000023.11:g.101407786G>A
NG_007119.1:g.5178C>T
NG_016327.1:g.4584G>A
NM_000169.3:c.118C>TMANE SELECT
NM_001199973.2:c.301-4150G>A
NM_001199974.2:c.178-4150G>A
NM_001406747.1:c.118C>T
NM_001406748.1:c.118C>T
NM_001406749.1:c.118C>T
NP_000160.1:p.Pro40Ser
NP_000160.1:p.Pro40Ser
NP_001393676.1:p.Pro40Ser
NP_001393677.1:p.Pro40Ser
NP_001393678.1:p.Pro40Ser
LRG_672t1:c.118C>T
LRG_672:g.5178C>T
LRG_672p1:p.Pro40Ser
NC_000023.10:g.100662774G>A
NM_000169.2:c.118C>T
NR_164783.1:n.140C>T
NR_176252.1:n.140C>T
NR_176253.1:n.140C>T
P06280:p.Pro40Ser
p.P40S

Protein change:

P40S; PRO40SER

Links:

UniProtKB: P06280#VAR_000434; OMIM: 300644.0009; dbSNP: rs104894831

NCBI 1000 Genomes Browser:

rs104894831

Molecular consequence:

NM_001199973.2:c.301-4150G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.178-4150G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.118C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406747.1:c.118C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406748.1:c.118C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406749.1:c.118C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.140C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176252.1:n.140C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176253.1:n.140C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Functional consequence:

effect on protein activity [Variation Ontology: 0053]

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
SCV000031698	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1990)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000917438	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 8, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9452111, 26415523, 25974833, 28360401, 2152885 Citation Link,
SCV002054461	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002782859	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2022)	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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Mutation analysis in 11 French patients with Fabry disease.

Guffon N, Froissart R, Chevalier-Porst F, Maire I.

Hum Mutat. 1998;Suppl 1:S288-90. No abstract available.

PubMed [citation]

PMID:: 9452111

Functional and Clinical Consequences of Novel α-Galactosidase A Mutations in Fabry Disease.

Lukas J, Scalia S, Eichler S, Pockrandt AM, Dehn N, Cozma C, Giese AK, Rolfs A.

Hum Mutat. 2016 Jan;37(1):43-51. doi: 10.1002/humu.22910. Epub 2015 Oct 27.

PubMed [citation]

PMID:: 26415523

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000031698.1

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

Description

Koide et al. (1990) described a pro40-to-ser (P40S) mutation in exon 1 of the GLA gene in a patient with Fabry disease (301500) and no detectable alpha-galactosidase A activity.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	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, SCV000917438.2

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

Description

Variant summary: GLA c.118C>T (p.Pro40Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183435 control chromosomes (gnomAD). c.118C>T has been reported in the literature in male individuals affected with Fabry Disease, some of whom have no detectable alpha-GLA activity reported (e.g. Koide_1990, Guffon_1998, Guitierrez-Amavizca_2017). Females who are heterozygous for the variant have been shown to have some associated mild phenotype, which may be in part due to X-chromosome inactivation (e.g. Koide_1990, Echevarria_2015). These data indicate that the variant is likely to be associated with disease. Experimental studies expressing the variant in vitro and examining fibroblasts derived from a hemizygous patient, show that the variant results in <1% of normal activity (e.g. Koide_1990, Lukas_2015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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 Genome-Nilou Lab, SCV002054461.1

#	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, SCV002782859.1

#	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 16, 2024

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