rs28935197

Variant names:

• chrX-101398942-T-C
• rs28935197
• NM_000169.3:c.644A>G
• GLA p.Asn215Ser

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+13 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM5PP3PP5_Strong

The NM_000169.3(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 cumulative frequency of 0.0000349 (AC=38) in the gnomAD database across 1,089,867 control chromosomes, including 11 hemizygotes. The grpmax filtering allele frequency (95% CI) is 0.0000327. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.02). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000543776: Experimental studies have shown that this missense change affects GLA function (PMID:16773563, 17555407, 21598360)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.N215K: Likely_pathogenic (ClinVar VariationId 3910027, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.N215D: Uncertain_significance (ClinVar VariationId 4087448, 1 star); p.N215H: Uncertain_significance (ClinVar VariationId 179331, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000035 (0 hom. 11 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27
• Conservation: PhyloP100: 8.02
• Publications: 219 publications found

Genes affected

GLA (HGNC:4296): ()

GLA Gene-Disease associations (from GenCC):

• Fabry disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Natera, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet, ClinGen

RPL36A-HNRNPH2 (HGNC:48349): ()

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000543776: Experimental studies have shown that this missense change affects GLA function (PMID: 16773563, 17555407, 21598360).; SCV001422796: "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; SCV004357520: 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; SCV004821932: 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).; SCV000207827: 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); SCV000925088: 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").; SCV004563354: Functional analyses demonstrate that enzyme with this variant has reduced stability/activity (Ishii 2007, Spada 2006).; SCV000739938: 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, 2006; Wu, 2011; Ishii, 2007; Ebrahim, 2012).; SCV000198194: Multiple functional studies have shown that the p.Asn215Ser variant protein has reduced enzymatic activity (Mills 2005, Ishii 2007, Wu 2011, Ebrahim 2012, Tian 2013).
	PM1Mutational hot spot or critical domain		UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 40 pathogenic, 0 benign rare missense variants (OR vs. background: 405.0).; ±8 AA neighbourhood: 22 pathogenic, 0 benign (OR vs. background: 225.0).
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.N215K: Likely_pathogenic (ClinVar VariationId 3910027, 1 star); Other variants at the same amino acid residue (not pathogenic): p.N215D: Uncertain_significance (ClinVar VariationId 4087448, 1 star); p.N215H: Uncertain_significance (ClinVar VariationId 179331, 2 stars)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (27/27 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000169.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GLA NM_000169.3	MANE Select	c.644A>G p.Asn215Ser	missense	Exon 5 of 7	Prot: NP_000160.1 UniProt:
	GLA NM_001406747.1		c.767A>G p.Asn256Ser	missense	Exon 6 of 8	Prot: NP_001393676.1 UniProt:
	GLA NM_001406748.1		c.644A>G p.Asn215Ser	missense	Exon 5 of 6	Prot: NP_001393677.1 UniProt:

GLA NM_000169.3

MANE Select

HGVSc / HGVSpc.644A>Gp.Asn215Ser

Exon rankExon 5 of 7

missense

Prot: NP_000160.1UniProt: P06280Q53Y83

GLA NM_001406747.1

HGVSc / HGVSpc.767A>Gp.Asn256Ser

Exon rankExon 6 of 8

missense

Prot: NP_001393676.1UniProt: A0A3B3IUC4

GLA NM_001406748.1

HGVSc / HGVSpc.644A>Gp.Asn215Ser

Exon rankExon 5 of 6

missense

Prot: NP_001393677.1UniProt: A0A6Q8PHD1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GLA ENST00000218516.4	TSL:1MANE Select	c.644A>G p.Asn215Ser	missense	Exon 5 of 7	Prot: ENSP00000218516.4 UniProt:
	RPL36A-HNRNPH2 ENST00000409170.3	TSL:4	c.300+3485T>C	intron	Intron 4 of 4	Prot: ENSP00000386655.4 UniProt:
	GLA ENST00000649178.1		c.767A>G p.Asn256Ser	missense	Exon 6 of 8	Prot: ENSP00000498186.1 UniProt:

GLA ENST00000218516.4

TSL:1MANE Select

HGVSc / HGVSpc.644A>Gp.Asn215Ser

Exon rankExon 5 of 7

missense

Prot: ENSP00000218516.4UniProt: P06280

RPL36A-HNRNPH2 ENST00000409170.3

TSL:4

HGVSc / HGVSpc.300+3485T>C

Exon rankIntron 4 of 4

intron

Prot: ENSP00000386655.4UniProt: H7BZ11

GLA ENST00000649178.1

HGVSc / HGVSpc.767A>Gp.Asn256Ser

Exon rankExon 6 of 8

missense

Prot: ENSP00000498186.1UniProt: A0A3B3IUC4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:23
GnomAD2 exomes	AF: 0.00000545	AC:1	Hom:	AN:183422	Cov:
GnomAD4 exome	AF: 0.0000349	AC:38	Hom:0	AN:1089867	Cov:29
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:23
TOPMed (Bravo)	AF: 0.00000756	AC:2	Hom:1	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00215	AC:104	Hom:0	AN:48418	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000238	1	41944	0.0000299	2	66798
SCHEMA(Schizophrenia)	0.0000295	2	67786	0.00	0	133138

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
15	-	-	Fabry disease (15)
9	-	-	not provided (9)
1	-	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Fabry disease;C0007194:Hypertrophic cardiomyopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Benign	0.096
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
CardioboostCm	Uncertain	0.59
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Uncertain	0.95	D
FuncVEP CTI	Pathogenic	0.47
GPN-Star LLR	N/A	-5.3
GPN-Star score	N/A	5.3
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	29/71	disease causing (ClinVar)
MutationAssessor	Uncertain	2.8	M
PhyloP100	Pathogenic	8.0
popEVE	Benign	-4.4
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0060	D
Varity_R	N/A	0.87
VESM-3B	Benign	-8.0

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040
SpliceAI score (max)	Benign	0.030	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs28935197;

hg19: chrX-100653930;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar