Submissions for variant NM_000512.5(GALNS):c.319G>A (p.Ala107Thr)

gnomAD frequency: 0.00002  dbSNP: rs763184657

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	RCV001578288	SCV001547656	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	research	In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_moderate); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); very low frequency in gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001578288	SCV003278936	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-09-03	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 1048185). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 107 of the GALNS protein (p.Ala107Thr). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is present in population databases (rs763184657, gnomAD 0.005%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 15241807, 32216080). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331129	SCV004039173	pathogenic	Morquio syndrome	2023-08-23	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.319G>A (p.Ala107Thr) 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. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 245626 control chromosomes (gnomAD). c.319G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (examples: Tomatsu_2004, Wang_2010, Al Jasmi_2012, Cozma_2015, Caciotti_2015). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15241807, 26147980, 23430803, 20574428, 25545067). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.