Submissions for variant NM_000512.5(GALNS):c.374C>T (p.Pro125Leu)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001095388	SCV001190351	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A		criteria provided, single submitter	clinical testing	A compound heterozygous missense variation in exon 4 of the GALNS gene that results in the amino acid substitution of Leucine for Proline at amino acid position 125 was detected. The observed variant c.374C>T (p.Pro125Leu) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant is damaging by LRT and MutationTaster2. The reference codon is conserved across species. The allele frequency of the variant is 0.00000399 in gnomAD Exomes. In summary, the variant meets our criteria to be classified as likely pathogenic.
Invitae	RCV001095388	SCV001386062	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 125 of the GALNS protein (p.Pro125Leu). This variant is present in population databases (rs746949976, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 9375852, 15241807, 24035930, 30458289). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 873151). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALNS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALNS function (PMID: 10814710). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001095388	SCV001547671	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	research	In vitro and in vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low to null in vitro enzymatic activity; PS3_moderate); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Fulgent Genetics, Fulgent Genetics	RCV001095388	SCV002811697	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2022-03-01	criteria provided, single submitter	clinical testing

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