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NM_000169.3(GLA):c.647A>G (p.Tyr216Cys) AND Fabry disease

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Sep 4, 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:
RCV000822976.17

Allele description [Variation Report for NM_000169.3(GLA):c.647A>G (p.Tyr216Cys)]

NM_000169.3(GLA):c.647A>G (p.Tyr216Cys)

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.647A>G (p.Tyr216Cys)
HGVS:
  • NC_000023.11:g.101398939T>C
  • NG_007119.1:g.14025A>G
  • NM_000169.3:c.647A>GMANE SELECT
  • NM_001199973.2:c.300+3482T>C
  • NM_001199974.2:c.177+7117T>C
  • NM_001406747.1:c.770A>G
  • NM_001406748.1:c.647A>G
  • NP_000160.1:p.Tyr216Cys
  • NP_000160.1:p.Tyr216Cys
  • NP_000160.1:p.Tyr216Cys
  • NP_001393676.1:p.Tyr257Cys
  • NP_001393677.1:p.Tyr216Cys
  • LRG_672t1:c.647A>G
  • LRG_672:g.14025A>G
  • LRG_672p1:p.Tyr216Cys
  • NC_000023.10:g.100653927T>C
  • NM_000169.2:c.647A>G
  • NR_164783.1:n.726A>G
  • NR_176252.1:n.577A>G
  • NR_176253.1:n.784A>G
  • p.Y216C
Protein change:
Y257C
Links:
dbSNP: rs398123217
NCBI 1000 Genomes Browser:
rs398123217
Molecular consequence:
  • NM_001199973.2:c.300+3482T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001199974.2:c.177+7117T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000169.3:c.647A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406747.1:c.770A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406748.1:c.647A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_164783.1:n.726A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176252.1:n.577A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176253.1:n.784A>G - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000963808Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Sep 4, 2023)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002054424Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jul 15, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Functional studies of new GLA gene mutations leading to conformational Fabry disease.

Filoni C, Caciotti A, Carraresi L, Cavicchi C, Parini R, Antuzzi D, Zampetti A, Feriozzi S, Poisetti P, Garman SC, Guerrini R, Zammarchi E, Donati MA, Morrone A.

Biochim Biophys Acta. 2010 Feb;1802(2):247-52. doi: 10.1016/j.bbadis.2009.11.003. Epub 2009 Nov 24.

PubMed [citation]
PMID:
19941952
PMCID:
PMC3056268

[Clinical manifestations and mutation study in 16 Chinese patients with Fabry disease].

Meng Y, Zhang WM, Shi HP, Wei M, Huang SZ.

Zhonghua Yi Xue Za Zhi. 2010 Mar 2;90(8):551-4. Chinese.

PubMed [citation]
PMID:
20367968
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000963808.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GLA function (PMID: 19941952). 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. ClinVar contains an entry for this variant (Variation ID: 92561). This missense change has been observed in individual(s) with Fabry disease (PMID: 19941952, 20367968, 27560961, 28756410; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 216 of the GLA protein (p.Tyr216Cys).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Genome-Nilou Lab, SCV002054424.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024