ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.644A>G (p.Asn215Ser) (rs28935197)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000157896 SCV000110129 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844705 SCV000198194 pathogenic Fabry disease; Hypertrophic cardiomyopathy 2014-04-02 criteria provided, single submitter clinical testing The p.Asn215Ser variant in GLA has been reported in >20 individuals, both male a nd female, with a clinical diagnosis of HCM and/or cardiac Fabry disease, and at least one male with features of classic Fabry disease (Davies 1993, Eng 1994, T opalaglu 1999, Walsh 2017, Oder 2017, LMM unpublished data). This variant has be en identified in 1/80091 of European chromosomes by the Genome Aggregation Datab ase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28935197). Multiple funct ional studies have shown that the p.Asn215Ser variant protein has reduced enzyma tic activity (Mills 2005, Ishii 2007, Wu 2011, Ebrahim 2012, Tian 2013). This va riant has also been reported in ClinVar (Variation ID#10730). In summary, this v ariant meets criteria to be classified as pathogenic for hypertrophic cardiomyop athy based upon presence in probands, very low frequency in controls, and functi onal evidence. ACMG criteria applied: PS3, PM2, PS4
GeneDx RCV000157896 SCV000207827 pathogenic not provided 2016-12-29 criteria provided, single submitter clinical testing The N215S mutation in the GLA gene has been previously reported in multiple patients diagnosed with Fabry disease (Davies J et al., 1993; Mills K et al., 2005; Schafer E et al., 2005; Spada M et al., 2006). Also, Hagege et al. (2011) identified the N215S mutation in a male patient with apparently isolated HCM, who did not exhibit features of classic Fabry disease. This patient also was found to have two maternal half-brothers with the N215S mutation and left ventricular hypertrophy, but no report of other signs of Fabry disease (Hagege A et al., 2011). N215S is thought to disrupt a protein glycosylation site (Asn-Tyr-Thr), which likely alters the pattern of glycolsylation in alpha-galactosidase A (Davies J et al., 1993).
Invitae RCV000011477 SCV000543776 pathogenic Fabry disease 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 215 of the GLA protein (p.Asn215Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous individuals and families affected with Fabry disease (FD), and has also been observed in asymptomatic or mild late-onset individuals that show symptoms primarily confined to the heart (PMID:8395937, 15712228, 18849176, 11531969, 11914245, 15091117, 15702404). ClinVar contains an entry for this variant (Variation ID: 10730). This variant is located at a highly conserved consensus N-glycosylation site and has been shown to decrease protein stability (PMID: 16773563, 17555407, 21598360). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000011477 SCV000611200 pathogenic Fabry disease 2017-05-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618059 SCV000739938 pathogenic Cardiovascular phenotype 2017-05-12 criteria provided, single submitter clinical testing Good segregation with disease (lod 1.5-3 = 5-9 meioses);Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Integrated Genetics/Laboratory Corporation of America RCV000011477 SCV000917441 pathogenic Fabry disease 2019-04-08 criteria provided, single submitter clinical testing Variant summary: GLA c.644A>G (p.Asn215Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-06 in 178708 control chromosomes (gnomAD). c.644A>G has been reported in the literature in multiple individuals affected with Fabry Disease. The variant has been identified in numerous patients and families with Fabry disease and is considered a known recurrent mutation that is associated with later-onset disease. A recent multi-center study of 125 Fabry disease patients with this mutation reported their study "confirms that p.N215S is a disease-causing Fabry mutation with severe clinical manifestations essentially limited to the heart until late adulthood, especially in males."(Germain_2018) Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics RCV000157896 SCV000928264 pathogenic not provided 2019-03-05 criteria provided, single submitter clinical testing
OMIM RCV000011477 SCV000031709 pathogenic Fabry disease 1993-12-01 no assertion criteria provided literature only
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000157896 SCV000800936 pathogenic not provided 2017-02-27 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000157896 SCV000925088 pathogenic not provided 2016-06-06 no assertion criteria provided provider interpretation 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.
Broad Institute Rare Disease Group,Broad Institute RCV000011477 SCV001422796 pathogenic Fabry disease 2020-01-22 no assertion criteria provided curation The p.Asn215Ser variant in GLA has been reported in at least 15 individuals from the literature with Fabry Disease (PMID:21598360, 10666480, 26047621, 23935525, 29621274), segregated with disease in 6 affected relatives from 1 family (PMID: 23818648), and has been identified in 0.001221% (1/81881) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28935197). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as pathogenic by multiple sources including Eurofins Clinical Diagnostics, Ambry Genetics, Fulgent Genetics, GeneDx, Invitae, Laboratory for Molecular Medicine (Partners Healthcare), Mayo Clinic, and OMIM (VariationID:10730). In vitro functional studies provide evidence of decreased enzymatic activity and protein stability, and therefore the p.Asn215Ser variant may impact protein function (PMID: 23935525, 23568732, 21972175, 21598360, 17555407,15702404, 16773563). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual hemizygous for this variant is highly specific for Fabry disease based on the classic phenotype consistent with disease (PMID: 30023289, 29621274,15895718, 7504405, 27532257, 26047621, 23935525, 15702404, 10666480, 7911050, 15091117, 11914245, 11531969, 18849176, 15712228, 21062768, 16773563, 23568732, 8395937). In summary, this variant meets criteria to be classified as pathogenic for Fabry disease based on multiple reports in the literature and ClinVar, reduced enzymatic activity in functional studies, low frequency in the general populaiton, and computational and conservation data. ACMG/AMP Criteria applied: PP4_moderate, PS3_Moderate, PS4, PP3, PP1, PM2_supporting (Richards 2015).

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