Submissions for variant NM_000512.5(GALNS):c.423-11_425del

Total submissions: 2

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	RCV003312991	SCV004011718	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-06-24	criteria provided, single submitter	clinical testing	A homozygous 14 base pair deletion in Intron 4 of the GALNS gene that results in a frameshift and premature truncation of the protein 382 amino acids downstream to codon 141 was detected. The observed variant c.423-11_425del (p.Trp141CysfsTer382) in intron has not been reported in the 1000 genomes and gnomAD databases. The in-silico prediction of the variant is disease causing by Mutation Taster. In summary, the variant meets our criteria to be classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003312991	SCV004320563	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-08-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GALNS protein in which other variant(s) (p.His142Leu) have been determined to be pathogenic (PMID: 20574428, 25252036, 25545067, 29731656, 30094185). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 2571592). This variant has not been reported in the literature in individuals affected with GALNS-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 5 (c.423-11_425del) of the GALNS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GALNS are known to be pathogenic (PMID: 12442278).