Submissions for variant NM_024312.5(GNPTAB):c.2957G>A (p.Arg986His)

dbSNP: rs776312538

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001175109	SCV002318284	likely pathogenic	Mucolipidosis type II; Pseudo-Hurler polydystrophy	2023-08-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 986 of the GNPTAB protein (p.Arg986His). This variant is present in population databases (rs776312538, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of GNPTAB-related conditions (PMID: 30882951, 32651481). ClinVar contains an entry for this variant (Variation ID: 917833). 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 GNPTAB protein function. This variant disrupts the p.Arg986 amino acid residue in GNPTAB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22495880; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003117804	SCV003801185	likely pathogenic	Mucolipidosis	2023-01-27	criteria provided, single submitter	clinical testing	Variant summary: GNPTAB c.2957G>A (p.Arg986His) results in a non-conservative amino acid change located in the Stealth protein CR3, conserved region 3 (IPR031357) 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 4e-06 in 251290 control chromosomes (gnomAD). c.2957G>A has been reported in the literature in a homozygous individual affected with Mucolipidosis (Pasumarthi_2020). In addition, other missense changes affecting the same amino acid (i.e. R986C/G/S) have been reported in individuals affected with Mucolipidosis (HGMD), suggesting clinical importance for this residue. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, in vitro functional studies reported that a different missense affecting this amino acid residue (R986C) almost completely abolished enzyme activity (Danyukova_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	RCV001175109	SCV001338687	likely pathogenic	Mucolipidosis type II; Pseudo-Hurler polydystrophy	2019-01-01	no assertion criteria provided	research