NM_000169.3(GLA):c.613C>A (p.Pro205Thr) AND Fabry disease

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 11, 2023
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:: RCV000153322.27

Allele description

NM_000169.3(GLA):c.613C>A (p.Pro205Thr)

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.613C>A (p.Pro205Thr)

HGVS:

NC_000023.11:g.101400692G>T
NG_007119.1:g.12272C>A
NM_000169.3:c.613C>AMANE SELECT
NM_001199973.2:c.300+5235G>T
NM_001199974.2:c.177+8870G>T
NM_001406747.1:c.736C>A
NM_001406748.1:c.613C>A
NP_000160.1:p.Pro205Thr
NP_000160.1:p.Pro205Thr
NP_001393676.1:p.Pro246Thr
NP_001393677.1:p.Pro205Thr
LRG_672t1:c.613C>A
LRG_672:g.12272C>A
LRG_672p1:p.Pro205Thr
NC_000023.10:g.100655680G>T
NM_000169.2:c.613C>A
NM_000169.2:c.613C>A
NR_164783.1:n.635C>A
NR_176253.1:n.750C>A
P06280:p.Pro205Thr
c.613C>A
p.P205T

Protein change:

P205T

Links:

UniProtKB: P06280#VAR_000463; dbSNP: rs397515870

NCBI 1000 Genomes Browser:

rs397515870

Molecular consequence:

NM_001199973.2:c.300+5235G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+8870G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.613C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406747.1:c.736C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406748.1:c.613C>A - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.635C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176253.1:n.750C>A - 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
SCV000058953	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Jun 7, 2016)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 8807334, 21598360, 8875188, 18205205, 26252393, 24386359, 15776423, 24033266
SCV002054428	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]
SCV002179136	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 11, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 8875188, 25611685, 27532257, 32150461, 18205205, 21598360, 8807334, 12175777, 15776423, 28728877, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000058953

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Jun 7, 2016)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV002054428

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]

SCV002179136

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 11, 2023)

germline

clinical testing

PubMed (11)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	3	2	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

Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase.

Warnock DG, Bichet DG, Holida M, Goker-Alpan O, Nicholls K, Thomas M, Eyskens F, Shankar S, Adera M, Sitaraman S, Khanna R, Flanagan JJ, Wustman BA, Barth J, Barlow C, Valenzano KJ, Lockhart DJ, Boudes P, Johnson FK.

PLoS One. 2015;10(8):e0134341. doi: 10.1371/journal.pone.0134341.

PubMed [citation]

PMID:: 26252393
PMCID:: PMC4529213

Comparative study of structural changes caused by different substitutions at the same residue on α-galactosidase A.

Saito S, Ohno K, Sakuraba H.

PLoS One. 2013;8(12):e84267. doi: 10.1371/journal.pone.0084267.

PubMed [citation]

PMID:: 24386359
PMCID:: PMC3873411

See all PubMed Citations (15)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000058953.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (8)

Description

The p.Pro205Thr variant in GLA has been reported in at least 4 individuals with Fabry disease and/or LVH (Blanch 1996, Davies 1996, Schafer 2005, Shimotori 2008 ) and has been identified by our laboratory in 1 family with HCM, segregating wi th one affected relative. It was absent from large population studies. In vitro assays showed the p.Pro205Thr variant was associated with decreased alpha-Gal ac tivity (~18% of normal enzyme activity), and that enzymatic levels increased aft er treatment with an experimental chaperone (Shimotori 2008, Wu 2011). However, these in vitro assays may not accurately represent biological function. In summa ry, this variant is likely to be pathogenic, though additional studies are requi red to fully establish its clinical significance.

#	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		3	not provided	2	not provided

From Genome-Nilou Lab, SCV002054428.1

#	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 Invitae, SCV002179136.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 205 of the GLA protein (p.Pro205Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical feature of Fabry disease (PMID: 8875188, 15776423, 18205205, 25611685, 27532257, 32150461). ClinVar contains an entry for this variant (Variation ID: 42456). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 18205205, 21598360). This variant disrupts the p.Pro205 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 8807334, 12175777, 15776423, 28728877), which suggests that this may be a clinically significant amino acid residue. 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

Last Updated: Sep 16, 2024

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