Submissions for variant NM_000512.5(GALNS):c.466T>C (p.Phe156Leu)

gnomAD frequency: 0.00001  dbSNP: rs1308500116

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633459	SCV000754688	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 156 of the GALNS protein (p.Phe156Leu). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with mucopolysaccharidosis IVa (PMID: 24726177; internal data). ClinVar contains an entry for this variant (Variation ID: 528321). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GALNS protein function with a positive predictive value of 95%. This variant disrupts the p.Phe156 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been observed in individuals with GALNS-related conditions (PMID: 9298823, 9521421), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000633459	SCV001547705	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	research	In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_moderate); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); very low frequency in gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222567	SCV002500599	pathogenic	Morquio syndrome	2022-03-23	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.466T>C (p.Phe156Leu) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251344 control chromosomes (gnomAD). c.466T>C has been reported in the literature in at least two homozygous individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (Examples: Cozma_2015 and Morrone_2014). Cozma_2015 demonstrated that GALINS activity in leucocytes from the homozygous individual was <1 (Normal range 107-198 nmol MU/mg protein). These data indicate that the variant is very likely to be associated with disease. Additionally, other missense variants in the same residue (F156S and F156C) have been reported in the Human Gene Mutation Database in association with Mucopolysaccharidosis Type IVA (PMID: 9521421, 9298823), supporting the functional importance of this residue of the protein. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000633459	SCV002786384	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-02-26	criteria provided, single submitter	clinical testing
GeneDx	RCV003151799	SCV003840723	likely pathogenic	not provided	2023-03-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24120057, 24726177, 26147980)