Submissions for variant NM_000512.5(GALNS):c.1052C>T (p.Ala351Val)

gnomAD frequency: 0.00002  dbSNP: rs761386453

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001578593	SCV001547886	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	curation	In vitro functional studies supportive of a damaging effect on the gene product (low in vitro enzymatic activity; PS3_supporting); very low frequency in gnomAD v2.1.1 (PM2_moderate)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844287	SCV002103524	uncertain significance	not specified	2022-02-16	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.1052C>T (p.Ala351Val) results in a non-conservative amino acid change located in the Sulfatase N-terminal domain (IPR000917) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 223600 control chromosomes (gnomAD). The variant, c.1052C>T, has been reported in the literature in an Italian patient affected with a severe form of Mucopolysaccharidosis Type IVA (Morquio Syndrome A), however, no second allele was reported (Tomatsu_1997). This publication also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant caused severely reduced enzyme activity in transiently transfected fibroblast as compared with fibroblasts transfected with normal cDNA (Tomatsu_1997). One ClinVar submitter has assessed the variant since 2014, and classified it as a VUS. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.