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NM_000169.3(GLA):c.644A>G (p.Asn215Ser) AND not provided

Germline classification:
Pathogenic (8 submissions)
Last evaluated:
Oct 16, 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:
RCV000157896.28

Allele description [Variation Report for NM_000169.3(GLA):c.644A>G (p.Asn215Ser)]

NM_000169.3(GLA):c.644A>G (p.Asn215Ser)

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.644A>G (p.Asn215Ser)
Other names:
p.N215S:AAT>AGT
HGVS:
  • NC_000023.11:g.101398942T>C
  • NG_007119.1:g.14022A>G
  • NM_000169.3:c.644A>GMANE SELECT
  • NM_001199973.2:c.300+3485T>C
  • NM_001199974.2:c.177+7120T>C
  • NM_001406747.1:c.767A>G
  • NM_001406748.1:c.644A>G
  • NP_000160.1:p.Asn215Ser
  • NP_000160.1:p.Asn215Ser
  • NP_000160.1:p.Asn215Ser
  • NP_001393676.1:p.Asn256Ser
  • NP_001393677.1:p.Asn215Ser
  • LRG_672t1:c.644A>G
  • LRG_672:g.14022A>G
  • LRG_672p1:p.Asn215Ser
  • NC_000023.10:g.100653930T>C
  • NM_000169.2(GLA):c.644A>G
  • NM_000169.2:c.644A>G
  • NR_164783.1:n.723A>G
  • NR_176252.1:n.574A>G
  • NR_176253.1:n.781A>G
  • P06280:p.Asn215Ser
  • p.N215S
Protein change:
N215S; ASN215SER
Links:
UniProtKB: P06280#VAR_000464; OMIM: 300644.0018; dbSNP: rs28935197
NCBI 1000 Genomes Browser:
rs28935197
Molecular consequence:
  • NM_001199973.2:c.300+3485T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001199974.2:c.177+7120T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000169.3:c.644A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406747.1:c.767A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406748.1:c.644A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_164783.1:n.723A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176252.1:n.574A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176253.1:n.781A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Functional consequence:
effect on protein activity [Variation Ontology: 0053]
Observations:
78

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000110129Eurofins Ntd Llc (ga)
criteria provided, single submitter

(EGL ClinVar v180209 classification definitions)
Pathogenic
(Aug 22, 2018)
germlineclinical testing

Citation Link,

SCV000207827GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Pathogenic
(Jun 2, 2022)
germlineclinical testing

Citation Link,

SCV000800936Mayo Clinic Laboratories, Mayo Clinic
no assertion criteria provided
Pathogenic
(Feb 27, 2017)
unknownclinical testing

SCV000925088Stanford Center for Inherited Cardiovascular Disease, Stanford University
no assertion criteria provided
Pathogenic
(Jun 6, 2016)
germlineprovider interpretation

SCV000928264Blueprint Genetics
criteria provided, single submitter

(Blueprint Genetics Variant Classification Scheme)
Pathogenic
(Mar 5, 2019)
germlineclinical testing

Citation Link,

SCV002024818Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jul 13, 2023)
germlineclinical testing

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

SCV004563354ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)
Pathogenic
(Oct 16, 2023)
germlineclinical testing

Citation Link,

SCV005198395Clinical Genetics Laboratory, Skane University Hospital Lund
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jul 6, 2023)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown78not providednot providednot providednot providedclinical testing, provider interpretation
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Eurofins Ntd Llc (ga), SCV000110129.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided78not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided78not providednot providednot provided

From GeneDx, SCV000207827.14

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

One of the most common later-onset Fabry disease GLA variants reported in individuals of European or North American descent, with cardiac manifestations as the typical presenting feature (Davies et al., 1993; Mills et al., 2005; Spada et al., 2006; Oder et al., 2017; Germain et al., 2018; Sheng et al., 2020); Published functional studies demonstrate a damaging effect as this variant is associated with reduced alpha-galactosidase A enzyme activity compared to wild-type (Spada et al. 2006; Wu et al. 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21972175, 25382311, 28943383, 31020198, 28793143, 15702404, 23568732, 17555407, 23935525, 25611685, 26047621, 27532257, 28728877, 27657681, 28988177, 24582695, 28649509, 31308319, 31956509, 30477121, 31447099, 32150461, 33673806, 32686758, 16773563, 21062768, 15886492, 31393666, 29649853, 29018006, 29621274, 8395937, 32435590, 30023289, 21598360)

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

From Mayo Clinic Laboratories, Mayo Clinic, SCV000800936.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000925088.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedprovider interpretationnot provided

Description

Given the strong case data and functional studies demonstrating impaired alpha-galactosidase enzyme activity we consider this variant to be disease-causing and we do feel it is suitable for establishing a diagnosis/carrier status of Fabry disease and assessing risk in healthy relatives ("predictive genetic testing"). There is strong case data for this variant, which has been reported in >9 unrelated cases of Fabry disease (not including this patient's family). We have seen the variant in a case of hypertrophic cardiomyopathy. Testing was done at Invitae. The variant has been reported in cases of "variant" phenotypes of Fabry disease, such as cases with isolated cardiac or renal disease, but has also been reported in classic cases. Please note that given the robust case data, the literature review performed in this case was not comprehensive. Eng et al., 1993 from the Desnick group at Mount Sinai reported the Arg215Ser variant in 3 unrelated people with isolated cardiac involvement including left ventricular hypertrophy. Davies et al., 1993 reported the Arg215Ser variant in a patient with classic Fabry disease. Altarescu et al., 2001 reported the Arg215Ser variant in 4 patients from 3 families with signs of Fabry disease, two of whom had angiokeratomas and mucosal anhydrosis (related) and one of whom had a cardiac phenotype (unrelated). All were reported to have alpha-galactosidase A activity of <11% of controls. One compound heterozygous female had a renal phenotype and was noted to have 0.7% alpha-Gal A activity. Sachdev et al., 2002 reported 3 males with the Arg215Ser variant and low alpha-Gal A activity in a study screening men with HCM for Fabry disease. It was not clear whether they may have been related or not or if they had a pure cardiac phenotype or other manifestations. Shabeer et al., 2005 reported the Arg215Ser variant in a female. No specific case data was provided; however, it was noted that the females tested were from Fabry families with unknown variants or clinically suspected to be affected. Erdos et al., 2008 reported the Arg215Ser variant in a Hungarian family with Fabry disease. It was identified in 3 males and 6 females; specific segregation data was not provided. One of the females had severe renal disease with proteinuria diagnosed at 25 and was found to be homozygous for the variant as a result of consanguinity. She and two other family members were noted to not have cardiac involvement. This mutation affects a highly conserved, functional N-glycosylation consensus site of the enzyme, but the expressed enzyme retains some activity. This is consistent with clinical observations of some families with variant presentations confined to one organ system. There is no variation at codon 215 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 6/6/2016). The mean coverage at that site in ExAC is 80x with median coverage of 90x and over 95% of individuals with 30x coverage.

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

From Blueprint Genetics, SCV000928264.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Revvity Omics, Revvity, SCV002024818.3

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004563354.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The GLA c.644A>G; p.Asn215Ser variant (rs28935197) is reported in the literature in numerous individuals and families affected with Fabry disease, typically with later onset and cardiac specific presentation (Eng 1993, Ishii 2007, Lavalle 2018, Oder 2017, Spada 2006, Tomberli 2013). Functional analyses demonstrate that enzyme with this variant has reduced stability/activity (Ishii 2007, Spada 2006). This variant is also reported in ClinVar (Variation ID: 10730). It is only found on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.72). Based on available information, this variant is considered to be pathogenic. References: Eng CM et al. Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. Am J Hum Genet. 1993 Dec;53(6):1186-97. PMID: 7504405. Ishii S et al. Mutant alpha-galactosidase A enzymes identified in Fabry disease patients with residual enzyme activity: biochemical characterization and restoration of normal intracellular processing by 1-deoxygalactonojirimycin. Biochem J. 2007 Sep 1;406(2):285-95. PMID: 17555407. Lavalle L et al. Phenotype and biochemical heterogeneity in late onset Fabry disease defined by N215S mutation. PLoS One. 2018 Apr 5;13(4):e0193550. PMID: 29621274. Oder D et al. alpha-Galactosidase A Genotype N215S Induces a Specific Cardiac Variant of Fabry Disease. Circ Cardiovasc Genet. 2017 Oct;10(5):e001691. PMID: 29018006. Spada M et al. High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet. 2006 Jul;79(1):31-40. PMID: 16773563. Tomberli B et al. Coronary microvascular dysfunction is an early feature of cardiac involvement in patients with Anderson-Fabry disease. Eur J Heart Fail. 2013 Dec;15(12):1363-73. PMID: 23818648.

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

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005198395.1

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

Last Updated: Nov 3, 2024