Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 3billion | RCV001807887 | SCV002058139 | uncertain significance | Mucopolysaccharidosis, MPS-IV-A | 2022-01-03 | criteria provided, single submitter | clinical testing | A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001048261, PM5_M). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000331, PM2_M). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001844415 | SCV002103522 | likely benign | not specified | 2022-02-22 | criteria provided, single submitter | clinical testing | Variant summary: GALNS c.143T>C (p.Val48Ala) results in a non-conservative amino acid change located in the 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 0.00033 in 249368 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.0041 in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) phenotype (0.002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.143T>C in individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) and no experimental evidence demonstrating its impact on protein function have been reported. Although a different missense variant affecting the same amino acid (c.143T>G (p.Val48Gly)) is classified as likely pathogenic by our laboratory, however Gly is never observed as the reference amino acid at this position in ~120 species (see e.g. in HGMD), while several species have Ala in this position, which suggests that this missense change might not adversely affect protein function. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. |
| Labcorp Genetics |
RCV001807887 | SCV002366711 | benign | Mucopolysaccharidosis, MPS-IV-A | 2024-01-12 | criteria provided, single submitter | clinical testing |