NM_000169.3:c.937G>T

GLA · NP_000160.1:p.(Asp313Tyr) · NM_000169.3

GRCh37: chrX:100653420 C>A · GRCh38: chrX:101398432 C>A

Gene: GLA Transcript: NM_000169.3

Final call

Likely Benign

BS1 supporting BS2 supporting BS3 strong BP4 supporting BP6 supporting

Variant details

Gene

GLA

Transcript

NM_000169.3

Protein

NP_000160.1:p.(Asp313Tyr)

gnomAD AF

0.0037791393165428617 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000169.3:c.937G>T (p.Asp313Tyr) is a missense variant in exon 6 of GLA observed at high frequency in population databases: 0.304% in gnomAD v2.1 (624/205,260 alleles, 3 homozygotes) and 0.378% in gnomAD v4.1 (4,565/1,207,947 alleles, 10 homozygotes).

Well-established functional studies demonstrate D313Y is a pseudodeficiency allele retaining approximately 60% of wild-type alpha-galactosidase A activity with proper lysosomal localization. The enzyme is stable at lysosomal pH, and Lyso-Gb3 biomarker levels are normal in D313Y carriers.

ClinVar reports this variant as Benign by 10 clinical laboratories and Likely benign by 7, with only 4 reporting Uncertain significance and 2 reporting other. The majority consensus supports a benign interpretation.

Multiple in silico predictors support a benign interpretation: SpliceAI predicts no splicing impact (max delta = 0.00), and BayesDel score of 0.065 is in the benign range.

Based on the generic ACMG/AMP 2015 framework, the combined evidence includes BS1 (supporting benign), BS2 (supporting benign), BS3 (strong benign), BP4 (supporting benign), and BP6 (supporting benign). No pathogenic criteria are met. The overall classification is Benign.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant (c.937G>T, p.Asp313Tyr). The generic PVS1 framework (PMC6185798) only applies to null variants: nonsense, frameshift, or canonical ±1,2 splice consensus variants. Missense substitutions are outside the PVS1 decision tree scope.	pvs1_generic_framework
PS1	Not assessed	No pathogenic substitution at the same nucleotide position (c.937) was identified. PS1 requires a known pathogenic variant at the same nucleotide position with a different amino acid change; no such comparator exists in ClinVar or the literature for this residue.
PS2	Not assessed	No de novo data were identified in any of the reviewed publications or ClinVar submissions for this variant.
PS3	Not met	Functional studies in COS-7 cells demonstrate that D313Y retains approximately 60% of wild-type alpha-galactosidase A enzymatic activity with proper lysosomal localization; the enzyme is stable at lysosomal pH (4.6) but shows reduced activity at neutral pH (7.4). This is consistent with a hypomorphic/pseudodeficiency allele, not a complete loss of function. The Lyso-Gb3 biomarker data confirms D313Y is not clinically relevant for Fabry disease.	PMID:14635108 PMID:23430502
PS4	Not assessed	No case-control study with adequate statistical power comparing variant prevalence in Fabry disease cases versus controls was identified. The variant is common in population databases (0.3-0.4%), which would confound any case-control comparison.
PS5	Not assessed	Not applicable — skipped per instruction.
PM1	Not met	Residue Asp313 is located in an alpha-helix on the perimeter of the beta/alpha-barrel domain, distant from the active site and dimer interface. The residue is not evolutionarily conserved (Asp-313 occurs in only one mammalian alpha-Gal A ortholog). No mutational hotspot or critical functional domain was identified at this position. The variant does not lie in a statistically significant hotspot.	PMID:14635108
PM2	Not met	This variant is present in gnomAD at a frequency of 0.304% (v2.1: 624/205,260 alleles) and 0.378% (v4.1: 4,565/1,207,947 alleles). Under the non-VCEP threshold of <0.1% for PM2, this frequency substantially exceeds the cutoff; PM2 is not met.	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue comparator variants with confirmed pathogenicity were identified in ClinVar; automatic candidate harvesting was unable to confirm classic same-residue PM5 semantics.
PM6	Not assessed	Not applicable — skipped per instruction.
PP1	Not assessed	While PMID:23393592 reports family screening data for D313Y carriers with white matter lesions, the segregation data are insufficient to meet PP1 thresholds. The variant is too common in the general population to assess meaningful cosegregation without formal LOD scores.
PP2	Not met	GLA has numerous benign missense variants documented in population databases including D313Y itself. PP2 requires a gene where missense variants are a common disease mechanism and benign missense variation is low, which does not apply to GLA given the high frequency of benign missense variants observed.	gnomad_v2 gnomad_v4
PP3	Not met	In silico predictions are consistent with a benign interpretation. SpliceAI predicts no splicing impact (max delta score = 0.00). BayesDel score is 0.065, well below the typical damaging threshold of ~0.13. REVEL score is unavailable. No computational evidence supports a deleterious effect.	spliceai bayesdel
PP4	Not assessed	The variant has been observed in patients with diverse phenotypes (stroke, white matter lesions, cardiomyopathy, renal disease), but also in healthy controls at high population frequency. Phenotype specificity is insufficient to support PP4.	PMID:20110537 PMID:23393592
PP5	Not met	ClinVar reports this variant as Benign (10 clinical laboratories), Likely benign (7), and Uncertain significance (4). The majority classification is benign. PP5 requires a reputable source to report the variant as pathogenic, which is not the case here.	clinvar
BA1	Not met	The variant frequency in gnomAD is 0.304% (v2.1) and 0.378% (v4.1), which is below the BA1 threshold of >1% allele frequency. While common, the frequency does not reach the stand-alone benign threshold.	gnomad_v2 gnomad_v4
BS1	Met	This variant is present in gnomAD at an allele frequency of 0.304% (v2.1, 624/205,260 alleles, 3 homozygotes) and 0.378% (v4.1, 4,565/1,207,947 alleles, 10 homozygotes), with a grpmax filtering allele frequency of 0.405%. These frequencies exceed the non-VCEP BS1 threshold of >0.3%, supporting a benign interpretation for a fully penetrant X-linked disorder.	gnomad_v2 gnomad_v4
BS2	Met	This variant is observed in homozygous state in gnomAD: 3 homozygotes in v2.1 and 10 homozygotes in v4.1. Fabry disease is an X-linked disorder with full penetrance in hemizygous males. The presence of multiple homozygous individuals in a population database that screens out severe pediatric disease indicates this variant is observed in healthy adults and does not cause Fabry disease.	gnomad_v2 gnomad_v4
BS3	Met	Well-established functional studies demonstrate that D313Y is a pseudodeficiency allele, not a pathogenic variant. In COS-7 cells, D313Y retains approximately 60% of wild-type alpha-galactosidase A enzymatic activity, localizes properly to lysosomes, and is stable at lysosomal pH (4.6). The D313Y enzyme is not evolutionarily conserved and the substitution is structurally tolerated. Lyso-Gb3 biomarker levels are normal in D313Y carriers, confirming absence of glycolipid accumulation. D313Y was found in 0.45% of normal X-chromosomes in a control population.	PMID:14635108 PMID:23430502
BS4	Not assessed	No formal cosegregation studies with LOD scores were identified. Given the high population frequency of D313Y, meaningful cosegregation analysis is challenging.
BP1	N/A	This is a missense variant. BP1 applies only when a truncating variant in a gene where loss of function is the known disease mechanism would be expected to be pathogenic, but is observed as benign. D313Y is not a truncating variant.
BP2	Not assessed	No observation of this variant in trans with a known pathogenic GLA variant was identified in the reviewed literature. Given Fabry disease is X-linked, BP2 is less applicable but could be considered if observed in trans in a female.
BP3	N/A	Skipped — trivially not applicable (in-frame indels in repetitive regions).
BP4	Met	Multiple in silico predictors support a benign interpretation. SpliceAI predicts no splicing impact (max delta score = 0.00), indicating the nucleotide change does not create or disrupt splice sites. BayesDel score of 0.065 is in the benign range (below ~0.13 damaging threshold). While REVEL is unavailable, the concordance of available predictors supports a benign computational profile.	spliceai bayesdel
BP5	Not met	This variant has been extensively reported in the literature in association with Fabry disease, stroke, white matter lesions, and other phenotypes. It does not meet the BP5 criterion which requires the variant to be found in a case with an alternate molecular cause for disease. No such alternate cause was identified in the reviewed cases.
BP6	Met	ClinVar classifies this variant as Benign based on submissions from 10 clinical laboratories, with an additional 7 laboratories reporting Likely benign. Only 4 laboratories report Uncertain significance, and 2 report other. The majority consensus among clinical laboratories strongly supports a benign interpretation.	clinvar
BP7	N/A	This is a missense variant (c.937G>T, p.Asp313Tyr). BP7 applies only to synonymous variants with no predicted splice impact.

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