Submissions for variant NM_000512.5(GALNS):c.425A>T (p.His142Leu)

dbSNP: rs1288895691

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001037304	SCV001200713	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 142 of the GALNS protein (p.His142Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis IVA (PMID: 25545067, 29731656, 30094185, 34542925). ClinVar contains an entry for this variant (Variation ID: 836229). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.His142 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been observed in individuals with GALNS-related conditions (PMID: 20574428, 25252036, 25545067), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001037304	SCV001547693	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	curation	The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); located in a mutational hot spot and/or critical and well-established functional domain without benign variation (PM1_moderate); very low frequency in gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702591	SCV005202939	likely pathogenic	Morquio syndrome	2024-07-23	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.425A>T (p.His142Leu) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250976 control chromosomes (gnomAD). c.425A>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVA (e.g. Caciotti_2015, Tapiero-Rodriguez_2018, Moreno Giraldo_2018, Pachajoa_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25545067, 34542925, 29731656, 30094185). ClinVar contains an entry for this variant (Variation ID: 836229). Based on the evidence outlined above, the variant was classified as likely pathogenic.