Submissions for variant NM_000512.5(GALNS):c.3G>A (p.Met1Ile)

dbSNP: rs2143013681

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001578348	SCV001547569	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	curation	In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting); absent from gnomAD v2.1.1 (PM2_moderate)
Neuberg Centre For Genomic Medicine, NCGM	RCV001578348	SCV005690594	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A		criteria provided, single submitter	clinical testing	The observed stop lost c.3G>A (p.Met1?) variant in GALNS gene has not been previously reported in homozygous and compound heterozygous state in two individuals affected with mucopolysaccharidosis IVA (Bidchol AM et al. 2014; Dũng VC et al. 2013). Another stop lost variant in the same residue (c.1A>G | p.Met1?) was identified in patient affected with mucopolysaccharidosis IVA (Tomatsu S et al. 2004). The p.Met1? variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence (Polyphen - Benign, SIFT - Damaging and Mutation Taster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid at this position on GALNS gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The p.Met1? variant is predicted to disrupt the initiation codon, and thus potentially may interfere with protein expression. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. Functional studies are required to prove the pathogenicity for the variant, for these reasons, this variant has been classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001578348	SCV005838454	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-03-16	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the GALNS mRNA. The next in-frame methionine is located at codon 22. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with mucopolysaccharidosis IVA (PMID: 15241807). ClinVar contains an entry for this variant (Variation ID: 1048247). Studies have shown that disruption of the initiator codon alters GALNS gene expression (PMID: 15241807). For these reasons, this variant has been classified as Pathogenic.