Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Broad Center for Mendelian Genomics, |
RCV000258893 | SCV001430741 | uncertain significance | Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome | 2020-05-29 | criteria provided, single submitter | research | The heterozygous p.Pro1122Leu variant in TBCD was identified by our study, in the compound heterozygous state, along with another variant of uncertain significance, in 1 individual with arthrogryposis multiplex congenita with severe hypotonia, respiratory insufficiency, multiple brain abnormalities, polyneuropathy. The p.Pro1122Leu variant in TBCD has been reported in 7 individuals, including the proband mentioned above, with progressive, early-onset encephalopathy, with brain atrophy and thin corpus callosum (PMID: 31395954, 31240573, 27666374, 27666370) and segregated with disease in 2 affected relatives from 2 families (PMID: 27666374, 27666370). The presence of this variant in 2 affected homozygotes and in combination with reported variants of uncertain significance that are confirmed in trans, and in 5 individuals with encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum increases the likelihood that the p.Pro1122Leu variant is pathogenic (VariationID: 268170, 393181, 268173; PMID: 31395954, 31240573, 27666374, 27666370). This variant has also been reported in ClinVar as pathogenic by OMIM (Variation ID#: 268171). The p.Pro1122Leu variant has been identified in 0.06% (12/19446) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs755177846). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. In vitro functional studies provide some evidence that the p.Pro1122Leu variant may impact protein function (PMID: 27666374, 27666370). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3, PS3_moderate, PP1 (Richards 2015). |
| Invitae | RCV001859530 | SCV002197104 | pathogenic | not provided | 2023-12-26 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1122 of the TBCD protein (p.Pro1122Leu). This variant is present in population databases (rs755177846, gnomAD 0.06%). This missense change has been observed in individual(s) with progressive early-onset encephalopathy with brain atrophy and thin corpus callosum (PMID: 27666370, 27666374, 31395954). 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: 268171). 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) has been performed at Invitae 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 TBCD protein function. Experimental studies have shown that this missense change affects TBCD function (PMID: 27666370). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000258893 | SCV002511733 | pathogenic | Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome | 2022-04-26 | criteria provided, single submitter | clinical testing | Variant summary: TBCD c.3365C>T (p.Pro1122Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.9e-05 in 246440 control chromosomes (gnomAD). c.3365C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Encephalopathy, Early Onset and was shown to segregate with disease within affected families (Flex_2016, Miyake_2016, Tian_2019, Wojcik_2019, Chen_2021). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated an extremely reduced TBCD protein level and partial loss of protein binding capacity with other components (Flex_2016, Miyake_2016). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. |
| OMIM | RCV000258893 | SCV000328660 | pathogenic | Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome | 2016-11-16 | no assertion criteria provided | literature only |