Submissions for variant NM_000512.5(GALNS):c.841_867del (p.Thr281_Asn289del)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001578523	SCV001547805	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	curation	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_strong); located in a mutational hot spot and/or critical and well-established functional domain without benign variation (PM1_moderate); absent from gnomAD v2.1.1 (PM2_moderate); protein length changes as a result of in-frame deletions in a nonrepeat region (PM4_moderate)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001578523	SCV004535389	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-09-06	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 1048421). 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.Phe285del) have been determined to be pathogenic (PMID: 15241807, 24875751, 29731656). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has been observed in individual(s) with Morquio A syndrome (PMID: 8844220, 32993725). This variant is present in population databases (no rsID available, gnomAD 0.001%). This variant, c.841_867del, results in the deletion of 9 amino acid(s) of the GALNS protein (p.Thr281_Asn289del), but otherwise preserves the integrity of the reading frame.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987848	SCV004804418	pathogenic	Morquio syndrome	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.841_867del27 (p.Thr281_Asn289del) results in an in-frame deletion that is predicted to remove 9 amino acids from the encoded protein. The variant allele was found at a frequency of 4.3e-06 in 231084 control chromosomes (gnomAD). c.841_867del27 has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (examples: Tomatsu_1995, Bunge_1997, Fukuda_1996, Morrone_2014). 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: 7668283, 9298823, 8844220, 24726177). ClinVar contains an entry for this variant (Variation ID: 1048421). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001578523	SCV005641479	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-01-12	criteria provided, single submitter	clinical testing

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