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 starscriteria provided, multiple submitters, no conflicts
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno 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
This HGVS expression did not pass validation- 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
Assertion and evidence details
Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
---|---|---|---|---|---|---|
SCV000110129 | Eurofins Ntd Llc (ga) | criteria provided, single submitter (EGL ClinVar v180209 classification definitions) | Pathogenic (Aug 22, 2018) | germline | clinical testing | |
SCV000207827 | GeneDx | criteria provided, single submitter (GeneDx Variant Classification Process June 2021) | Pathogenic (Jun 2, 2022) | germline | clinical testing | |
SCV000800936 | Mayo Clinic Laboratories, Mayo Clinic | no assertion criteria provided | Pathogenic (Feb 27, 2017) | unknown | clinical testing | |
SCV000925088 | Stanford Center for Inherited Cardiovascular Disease, Stanford University | no assertion criteria provided | Pathogenic (Jun 6, 2016) | germline | provider interpretation | |
SCV000928264 | Blueprint Genetics | criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) | Pathogenic (Mar 5, 2019) | germline | clinical testing | |
SCV002024818 | Revvity Omics, Revvity | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jul 13, 2023) | germline | clinical testing | |
SCV004563354 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) | Pathogenic (Oct 16, 2023) | germline | clinical testing | |
SCV005198395 | Clinical Genetics Laboratory, Skane University Hospital Lund | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jul 6, 2023) | germline | clinical testing |
Summary from all submissions
Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
---|---|---|---|---|---|---|---|---|
not provided | germline | unknown | 78 | not provided | not provided | not provided | not provided | clinical testing, provider interpretation |
not provided | unknown | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
not provided | germline | yes | not provided | not provided | not provided | not provided | not provided | clinical testing |
Citations
PubMed
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.
- PMID:
- 25741868
- PMCID:
- PMC4544753
Details of each submission
From Eurofins Ntd Llc (ga), SCV000110129.8
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 78 | not provided | not provided | clinical testing | not provided |
# | 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 | 78 | not provided | not provided | not provided |
From GeneDx, SCV000207827.14
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not 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)
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Mayo Clinic Laboratories, Mayo Clinic, SCV000800936.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
# | 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 Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000925088.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | provider interpretation | not 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.
# | 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 |
From Blueprint Genetics, SCV000928264.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Revvity Omics, Revvity, SCV002024818.3
# | 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 | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004563354.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not 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.
# | 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 |
From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005198395.1
# | 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 | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
Last Updated: Nov 3, 2024