rs28935197

Positions:

chrX-101398942-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The ENST00000218516.4(GLA):c.644A>G(p.Asn215Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,089,867 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N215H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000035 ( 0 hom. 11 hem. )

Consequence

GLA
ENST00000218516.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:23

Conservation

PhyloP100: 8.02

Variant links:

Genes affected

GLA (HGNC:4296): (galactosidase alpha) This gene encodes a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. This enzyme predominantly hydrolyzes ceramide trihexoside, and it can catalyze the hydrolysis of melibiose into galactose and glucose. A variety of mutations in this gene affect the synthesis, processing, and stability of this enzyme, which causes Fabry disease, a rare lysosomal storage disorder that results from a failure to catabolize alpha-D-galactosyl glycolipid moieties. [provided by RefSeq, Jul 2008]

GLA links:

RPL36A-HNRNPH2 (HGNC:):

RPL36A-HNRNPH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in ENST00000218516.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.937

PP5

Variant X-101398942-T-C is Pathogenic according to our data. Variant chrX-101398942-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 10730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101398942-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3 linkuse as main transcript	c.644A>G	p.Asn215Ser	missense_variant	5/7	ENST00000218516.4	NP_000160.1
RPL36A-HNRNPH2	NM_001199973.2 linkuse as main transcript	c.300+3485T>C		intron_variant			NP_001186902.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4 linkuse as main transcript	c.644A>G	p.Asn215Ser	missense_variant	5/7	1	NM_000169.3	ENSP00000218516	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183422

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1089867

Hom.:

Cov.:

AF XY:

0.0000309

AC XY:

AN XY:

355965

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000443

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

Cov.:

Alfa

AF:

0.00499

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fabry disease

Pathogenic:12

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 14, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1993	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Medical Genetics, University of Torino	Nov 29, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 08, 2024	This missense variant replaces asparagine with serine at codon 215 of the GLA protein. Asn215 has been reported as one of the N-linked carbohydrate attachment sites; glycosylation at this site is crucial for the efficient trafficking of the GLA enzyme to the lysosome (PMID: 9620884, 15003450). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that this variant results in reduced GLA enzyme activity when expressed in HEK-293 or COS-7 cells (PMID: 16773563, 17555407, 21598360). This variant has been reported in many individuals affected with Fabry disease, predominantly with cardiac manifestations (left ventricular hypertrophy, arrhythmia) in later adulthood (PMID: 29649853, 32150461, 32435590, 32432376, 32963035, 33335842, 33807900, 35035949, 36087038, 37205992, 37480128, 38002959). This variant has also been reported in individuals affected with classic Fabry disease or renal impairment, but less frequently (PMID: 8395937, 29649853, 32435590, 35035949). It has been shown that this variant segregates with Fabry disease in multiple individuals from two families (PMID: 28943383). This variant has been identified in 1/183422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 01, 2024	This missense variant replaces asparagine with serine at codon 215 of the GLA protein. Asn215 has been reported as one of the N-linked carbohydrate attachment sites and glycosylation at this site is crucial for the efficient trafficking of the GLA enzyme to the lysosome (PMID: 9620884, 15003450). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in reduced GLA enzyme activity when expressed in HEK-293 or COS-7 cells (PMID: 16773563, 17555407, 21598360). This variant has been reported in many individuals affected with Fabry disease, predominantly with cardiac manifestations in late adulthood, especially in males (e.g. left ventricular hypertrophy, arrhythmia) (PMID: 29649853, 32150461, 32435590, 32432376, 32963035, 33335842, 33807900, 35035949, 36087038, etc.). Cases with classic Fabry disease or renal impairment have also been reported but less frequently (e.g. PMID: 8395937, 29649853, 32435590, 35035949). It has been shown that this variant segregates with Fabry disease in multiple individuals from two families (PMID: 28943383). This variant has been identified in 1/183422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 215 of the GLA protein (p.Asn215Ser). This variant is present in population databases (rs28935197, gnomAD 0.001%). This missense change has been observed in individuals with clinical features of Fabry disease (PMID: 8395937, 11531969, 11914245, 15091117, 15702404, 15712228, 18849176). ClinVar contains an entry for this variant (Variation ID: 10730). 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 not expected to disrupt GLA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 16773563, 17555407, 21598360). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 08, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0103 - Loss of function and dominant negative are known mechanisms of disease in this gene and are associated with Fabry disease (MIM#301500). Loss of function is a known mechanism of disease in males. Females can be affected but with variable severity unexplained by skewed X-inactivation (PMID: 31613176), suggested to be due to the dominant negative mechanism of some variants. Truncating variants in the last exon have been reported with a dominant negative mechanism in females. Gain of function has also been suggested; however more evidence is required (PMIDs: 8878432; 31613176). (I) 0109 - This gene is associated with X-linked disease. Both males and females have been reported with Fabry disease, though the latter are more rarely reported and tend to have milder disease (OMIM, PMID: 31613176). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a condition (0 heterozygotes, 0 homozygotes, 1 hemizygote). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated melibiase_2 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is a recurrent mutation associated with late-onset Fabry disease (ClinVar, PMIDs: 32435590; 29018006). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 06, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 27, 2017	- -
Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 06, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 05, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	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. -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Aug 18, 2021

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2023

The p.N215S pathogenic mutation (also known as c.644A>G), located in coding exon 5 of the GLA gene, results from an A to G substitution at nucleotide position 644. The asparagine at codon 215 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in patients with Fabry disease, hypertrophic cardiomyopathy (HCM), and renal disease (Davies JP et al. Hum Mol Genet. 1993;2(7):1051-3; Eng CM et al. Am J Hum Genet. 1993;53(6):1186-97; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Sugarman M et al. Mol Genet Metab Rep, 2018 Jun;15:43-45; Maron MS et al. Am. J. Med., 2018 02;131:200.e1-200.e8; Pasqualim G et al. Clin. Biochem., 2014 May;47:657-62; Militaru S et al. Curr Health Sci J Oct;45:272-277; Sheng B et al. Mol Genet Metab Rep, 2020 Sep;24:100596; Tian ML et al. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2013 Apr;30:185-8; Duro G et al. Int J Mol Sci, 2018 Nov;19; Sakuraba H et al. Mol Genet Metab Rep, 2018 Dec;17:73-79; Koulousios K et al. BMJ Open, 2017 Oct;7:e017098; Varela P et al. Orphanet J Rare Dis, 2020 01;15:30). This variant has also been observed to co-segregate with Fabry disease in multiple families (Tomberli B et al. Eur J Heart Fail. 2013;15(12):1363-73; Maron MS et al. Am. J. Med., 2018 02;131:200.e1-200.e8; Spada M et al. Am J Hum Genet. 2006;79(1):31-40). It has been reported in the heterozygous state in a woman with Fabry disease and progressive cardiac dysfunction, who also had another heterozygous variant in GLA (p.C202R, c.604T>C) (McConnell EJ et al. Eur Heart J Case Rep, 2018 Dec;2:yty122). Individuals with this alteration have been reported to have later age of onset and fewer extracardiac findings when compared to individuals with classic Fabry disease (Thomas A et al. Molec Gen and Metab. 2015 Feb;114(2):S113; Frustaci A et al. Circ Arrhythm Electrophysiol, 2015 Aug;8:799-805; Sugarman M et al. Mol Genet Metab Rep, 2018 Jun;15:43-45; Lavalle L et al. PLoS ONE, 2018 Apr;13:e0193550; Oder D et al. Circ Cardiovasc Genet, 2017 Oct;10; Germain DP et al. Mol Genet Genomic Med, 2018 Apr). In several functional in vitro analyses, this alteration has demonstrated a reduction in alpha-galactosidase A enzyme activity, suggesting variable expressivity among clinical phenotypes depending on residual enzyme activity (Spada M et al. Am J Hum Genet. 2006;79(1):31-40; Wu X et al. Hum. Mutat., 2011 Aug;32:965-77; Ishii S et al. Biochem. J., 2007 Sep;406:285-95; Ebrahim HY et al. J. Inherit. Metab. Dis., 2012 Mar;35:325-34). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Fabry disease;C0007194:Hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 02, 2014

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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

CardioboostCm

Uncertain

0.59

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

M;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.4

D;.

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0040

D;.

Sift4G

Uncertain

0.0060

D;.

Polyphen

0.048

B;.

Vest4

0.90

MutPred

0.80

Loss of catalytic residue at N215 (P = 0.0951);.;

MVP

0.99

MPC

0.73

ClinPred

0.73

GERP RS

6.0

Varity_R

0.87

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over