Submissions for variant NM_005908.4(MANBA):c.1499G>A (p.Arg500His)

gnomAD frequency: 0.00014  dbSNP: rs147542645

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002048507	SCV002300091	uncertain significance	Beta-D-mannosidosis	2022-08-20	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 500 of the MANBA protein (p.Arg500His). This variant is present in population databases (rs147542645, gnomAD 0.04%). This missense change has been observed in individual(s) with beta mannosidosis (PMID: 31115173). ClinVar contains an entry for this variant (Variation ID: 1515408). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
3billion	RCV002048507	SCV002521475	likely pathogenic	Beta-D-mannosidosis	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.021%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 3Cnet: 0.78). Same nucleotide change resulting in same amino acid change has been previously reported (PMID: 31115173). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002048507	SCV002768906	likely pathogenic	Beta-D-mannosidosis	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Beta-mannosidosis (MIM#248510). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 69 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2 & v3: 4 heterozygotes, 0 homozygotes). In addition, a deletion of this residue has been observed in gnomAD (v2: 2 heterozygotes, 0 homozygotes). (I) 0600 - Variant is located in the annotated glyco_hydro_2C domain (PDB). (I) 0710 - Another variant affecting this same residue comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Arg500del) has been reported 3 times as VUS by VKGL laboratory (ClinVar, LOVD). (I) 0803 - This variant has limited previous evidence of pathogenicity. Even though it was regarded as VUS in ClinVar and LOVD, it has been detected in an individual with β‐mannosidosis, in a compound heterozygote state (PMID: 31115173). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. In a patient compound heterozygote for this variant and p.(Trp192*), biochemical tests using 3 different biological sample types showed significantly lower β‐mannosidase activities (PMID: 31115173). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002048507	SCV005659891	likely pathogenic	Beta-D-mannosidosis	2024-03-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005238178	SCV005883256	uncertain significance	not specified	2024-12-17	criteria provided, single submitter	clinical testing	Variant summary: MANBA c.1499G>A (p.Arg500His) results in a non-conservative amino acid change located in the Glycoside hydrolase family 2, catalytic domain (IPR006103) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 250672 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MANBA causing Beta-D-mannosidosis, allowing no conclusion about variant significance. c.1499G>A has been reported in the literature in one individual affected with Beta-D-mannosidosis (Lund_2019). The report does not provide unequivocal conclusions about association of the variant with Beta-D-mannosidosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31115173). ClinVar contains an entry for this variant (Variation ID: 1515408). Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Computational Biology & Bioinformatics, University of California, San Diego	RCV004571983	SCV005049955	uncertain significance	Meniere disease	2024-06-03	no assertion criteria provided	research