NM_000169.3(GLA):c.620A>C (p.Tyr207Ser) AND Fabry disease

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: May 27, 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:: RCV000709851.8

Allele description [Variation Report for NM_000169.3(GLA):c.620A>C (p.Tyr207Ser)]

NM_000169.3(GLA):c.620A>C (p.Tyr207Ser)

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.620A>C (p.Tyr207Ser)

HGVS:

NC_000023.11:g.101400685T>G
NG_007119.1:g.12279A>C
NM_000169.3:c.620A>CMANE SELECT
NM_001199973.2:c.300+5228T>G
NM_001199974.2:c.177+8863T>G
NM_001406747.1:c.743A>C
NM_001406748.1:c.620A>C
NP_000160.1:p.Tyr207Ser
NP_000160.1:p.Tyr207Ser
NP_001393676.1:p.Tyr248Ser
NP_001393677.1:p.Tyr207Ser
LRG_672t1:c.620A>C
LRG_672:g.12279A>C
LRG_672p1:p.Tyr207Ser
NC_000023.10:g.100655673T>G
NM_000169.2:c.620A>C
NR_164783.1:n.642A>C
NR_176253.1:n.757A>C

Protein change:

Y207S

Links:

dbSNP: rs797044727

NCBI 1000 Genomes Browser:

rs797044727

Molecular consequence:

NM_001199973.2:c.300+5228T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+8863T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.620A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406747.1:c.743A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406748.1:c.620A>C - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.642A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176253.1:n.757A>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
SCV000840183	GenomeConnect, ClinGen	no classification provided	not provided	unknown	phenotyping only
SCV002288937	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 27, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21598360, 18698230, 19387866, 12175777, 15712228, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000840183

GenomeConnect, ClinGen

no classification provided

not provided

unknown

phenotyping only

SCV002288937

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(May 27, 2021)

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	phenotyping only

Citations

PubMed

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

Prediction of response of mutated alpha-galactosidase A to a pharmacological chaperone.

Shin SH, Kluepfel-Stahl S, Cooney AM, Kaneski CR, Quirk JM, Schiffmann R, Brady RO, Murray GJ.

Pharmacogenet Genomics. 2008 Sep;18(9):773-80. doi: 10.1097/FPC.0b013e32830500f4.

PubMed [citation]

PMID:: 18698230
PMCID:: PMC2657085

See all PubMed Citations (6)

Details of each submission

From GenomeConnect, ClinGen, SCV000840183.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002288937.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Tyr207 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 19387866), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this variant affects GLA protein function (PMID: 21598360). This variant has been observed in individual(s) with Fabry disease (PMID:18698230, 19387866, 12175777, 15712228). ClinVar contains an entry for this variant (Variation ID: 585078). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with serine at codon 207 of the GLA protein (p.Tyr207Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine.

#	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 29, 2024

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