Submissions for variant NM_000512.5(GALNS):c.1240C>T (p.Gln414Ter)

gnomAD frequency: 0.00001  dbSNP: rs757870208

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001358674	SCV001547935	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	curation	Nonsense variant (PVS1_very strong); in vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_moderate); very low frequency in gnomAD v2.1.1 (PM2_moderate)
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV001358674	SCV001554471	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-04-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001358674	SCV002044995	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001358674	SCV003825772	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2022-05-02	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001358674	SCV003936000	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-06-26	criteria provided, single submitter	clinical testing	A homozygous nonsense variant in exon 11 of the GALNS gene that results in a stop codon and premature truncation of the protein at codon 414 (p.Gln414Ter) was detected. This variant has not been reported in the 1000 genomes and has a MAF of 0.0008% in the gnomAD database. The in-silico predictions of the variant is damaging by MutationTaster2. In summary the variant meets our criteria to be classified as pathogenic
Labcorp Genetics (formerly Invitae), Labcorp	RCV001358674	SCV004297056	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln414*) in the GALNS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALNS are known to be pathogenic (PMID: 12442278). This variant is present in population databases (rs757870208, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Morquio A (PMID: 24726177). ClinVar contains an entry for this variant (Variation ID: 1048350). For these reasons, this variant has been classified as Pathogenic.