Submissions for variant NM_000512.5(GALNS):c.986A>C (p.His329Pro)

gnomAD frequency: 0.00002  dbSNP: rs760892654

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001349762	SCV001544122	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-02-23	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 329 of the GALNS protein (p.His329Pro). This variant is present in population databases (rs760892654, gnomAD 0.05%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 25252036). ClinVar contains an entry for this variant (Variation ID: 1045364). 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%. This variant disrupts the p.His329 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been observed in individuals with GALNS-related conditions (PMID: 34387910), 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	RCV001349762	SCV001547868	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	curation	Very low frequency in gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Genome-Nilou Lab	RCV001349762	SCV002044982	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV001349762	SCV002507160	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2022-05-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001349762	SCV004235105	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2023-02-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003490214	SCV004241544	likely pathogenic	Morquio syndrome	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.986A>C (p.His329Pro) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 249854 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (5.6e-05 vs 0.002), allowing no conclusion about variant significance. c.986A>C has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A; Bidchol_2014, Uttarilli_2019). 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: 25252036, 30408610). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=1) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV001349762	SCV005400810	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-06-22	criteria provided, single submitter	clinical testing	The missense c.986A>C(p.His329Pro) variant in GALNS gene has been reported in compound heterozygous state in individuals affected with Mucopolysaccharidosis IVA (Bidchol et. al., 2014). The observed variant has allele frequency of 0.006% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Pathogenic / Uncertain Significance (multiple submissions). Multiple lines of computational evidence (Polyphen - possibly damaging , SIFT - tolerated and MutationTaster - disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid change p.His329Pro in GALNS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid His at position 329 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS).
Fulgent Genetics, Fulgent Genetics	RCV001349762	SCV005641468	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-05-25	criteria provided, single submitter	clinical testing