Submissions for variant NM_000512.5(GALNS):c.692C>T (p.Ala231Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002766789	SCV003028195	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2022-02-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 231 of the GALNS protein (p.Ala231Val). This variant is present in population databases (rs34745339, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with GALNS-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALNS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479443	SCV004223215	uncertain significance	not specified	2023-11-28	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.692C>T (p.Ala231Val) results in a non-conservative amino acid change located in the sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251332 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.692C>T in individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) and no experimental evidence demonstrating its impact on protein function have been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35094026). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.