Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mendelics | RCV000492144 | SCV001135618 | likely pathogenic | Infantile liver failure syndrome 2 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001797736 | SCV002041749 | uncertain significance | not specified | 2023-11-16 | criteria provided, single submitter | clinical testing | Variant summary: NBAS c.680A>C (p.His227Pro) results in a non-conservative amino acid change located in the Neuroblastoma-amplified sequence, N-terminal domain (IPR029145) 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 251406 control chromosomes (gnomAD). c.680A>C has been reported in the literature as a compound heterozygous genotype in at-least two comprehensively genotyped siblings affected with Liver Failure Acute Infantile, Type 2, and has also been subsequently cited by others (example, Regateiro_2017, Khoreva_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33042920, 28576691). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Labcorp Genetics |
RCV001851285 | SCV002280159 | uncertain significance | not provided | 2024-10-16 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 227 of the NBAS protein (p.His227Pro). This variant is present in population databases (rs748880753, gnomAD 0.003%). This missense change has been observed in individual(s) with acute liver failure (PMID: 28576691). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 424843). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NBAS 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. |
| Gene |
RCV001851285 | SCV005370554 | likely pathogenic | not provided | 2024-04-05 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 33042920, 28576691) |
| Laboratory of Jean- |
RCV000492144 | SCV000564508 | pathogenic | Infantile liver failure syndrome 2 | no assertion criteria provided | clinical testing |