NM_000169.3(GLA):c.613C>G (p.Pro205Ala) AND Fabry disease

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 5, 2023
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:: RCV003097834.3

Allele description [Variation Report for NM_000169.3(GLA):c.613C>G (p.Pro205Ala)]

NM_000169.3(GLA):c.613C>G (p.Pro205Ala)

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>G (p.Pro205Ala)

HGVS:

NC_000023.11:g.101400692G>C
NG_007119.1:g.12272C>G
NM_000169.3:c.613C>GMANE SELECT
NM_001199973.2:c.300+5235G>C
NM_001199974.2:c.177+8870G>C
NM_001406747.1:c.736C>G
NM_001406748.1:c.613C>G
NP_000160.1:p.Pro205Ala
NP_000160.1:p.Pro205Ala
NP_001393676.1:p.Pro246Ala
NP_001393677.1:p.Pro205Ala
LRG_672t1:c.613C>G
LRG_672:g.12272C>G
LRG_672p1:p.Pro205Ala
NC_000023.10:g.100655680G>C
NM_000169.2:c.613C>G
NR_164783.1:n.635C>G
NR_176253.1:n.750C>G

Protein change:

P205A

Molecular consequence:

NM_001199973.2:c.300+5235G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+8870G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.613C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406747.1:c.736C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406748.1:c.613C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.635C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176253.1:n.750C>G - 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
SCV002983586	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 5, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 32813676, 8875188, 15776423, 18205205, 21598360, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002983586

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 5, 2023)

germline

clinical testing

PubMed (6)
[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

Citations

PubMed

Analysis of the alpha galactosidase gene: mutation profile and description of two novel mutations with extensive literature review in Turkish population.

Onay H, Bolat H, Kılıç Yıldırım G, Kose E, Kalkan Uçar S, Aşıkovalı S, Özkınay F, Çoker M.

J Pediatr Endocrinol Metab. 2020 Aug 19;33(10):1245-1250. doi: 10.1515/jpem-2020-0056. Review.

PubMed [citation]

PMID:: 32813676

Fabry disease: fourteen alpha-galactosidase A mutations in unrelated families from the United Kingdom and other European countries.

Davies JP, Eng CM, Hill JA, Malcolm S, MacDermot K, Winchester B, Desnick RJ.

Eur J Hum Genet. 1996;4(4):219-24.

PubMed [citation]

PMID:: 8875188

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV002983586.2

#	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 proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 205 of the GLA protein (p.Pro205Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 32813676). ClinVar contains an entry for this variant (Variation ID: 1711995). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLA protein function. This variant disrupts the p.Pro205 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8875188, 15776423, 18205205, 21598360). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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