Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001266809 | SCV001444988 | uncertain significance | Inborn genetic diseases | 2023-02-27 | criteria provided, single submitter | clinical testing | The c.1108G>C (p.V370L) alteration is located in coding exon 8 of the GMPPB gene. This alteration results from a G to C substitution at nucleotide position 1108, causing the valine (V) at amino acid position 370 to be replaced by a leucine (L). Based on data from gnomAD, the C allele has an overall frequency of 0.001% (3/249892) total alleles studied. The highest observed frequency was 0.003% (3/113388) of European (non-Finnish) alleles. This alteration has been reported with a second likely pathogenic alteration in the GMPPB gene in a patient with adult-onset myalgia, muscle weakness, foot drop, foot deformities, ocular myasthenia gravis, and myopathic changes on EMG (Sarkozy, 2018). This amino acid position is highly conserved in available vertebrate species. Functional studies suggests that the variant does not significantly alter protein abundance, but tends to form punctate aggregates that are susceptible to increased lysosomal degradation (Sarkozy, 2018; Tian, 2019). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Revvity Omics, |
RCV003132368 | SCV003816944 | uncertain significance | not provided | 2023-07-05 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV003770391 | SCV004580521 | uncertain significance | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14; Autosomal recessive limb-girdle muscular dystrophy type 2T | 2023-04-03 | criteria provided, single submitter | clinical testing | 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. Experimental studies have shown that this missense change affects GMPPB function (PMID: 31211170). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 985743). This variant is also known as c.1108G>C (p.Val370Leu). This missense change has been observed in individual(s) with GMPPB-related conditions (PMID: 29437916). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 343 of the GMPPB protein (p.Val343Leu). |