Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Diagnostics Division, |
RCV000416327 | SCV000494025 | likely pathogenic | Tarsal-carpal coalition syndrome | 2016-01-01 | criteria provided, single submitter | research | |
| Labcorp Genetics |
RCV002521489 | SCV003441960 | uncertain significance | not provided | 2022-09-12 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 204 of the NOG protein (p.Arg204Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tarsal-carpal coalition syndrome (PMID: 29159868). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 375295). 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 disruptive. 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. |
| Clinical Genomics Laboratory, |
RCV001254352 | SCV001427233 | likely pathogenic | Brachydactyly type B2; Symphalangism-brachydactyly syndrome; Tarsal-carpal coalition syndrome; Stapes ankylosis with broad thumbs and toes; Proximal symphalangism 1A | 2020-05-06 | no assertion criteria provided | clinical testing | The p.Arg204Gln variant in the NOG gene has been previously reported in 3 related individuals from 1 family with tarsal-carpal coalition syndrome. This variant co-segregated with disease in affected family members presenting with variable skeletal anomalies including proximal symphalangism and carpal and tarsal fusion (Das Bhowmik et al., 2018). The p.Arg204Gln variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Notably, a different amino acid change (p.Arg204Leu) has been previously reported at this residue, as well as amino acid changes at nearby residues (p.Leu203Pro, p.Trp205Cys), suggesting the p.Arg204Gln variant may occur in a mutational hotspot of the NOG gene. Computational tools predict that the p.Arg204Gln variant is deleterious; however, the accuracy of in silicoalgorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg204Gln variant as likely pathogenic for a NOG-related disorder in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PS2_Moderate; PM1_supporting; PM2; PP3] |