Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001365019 | SCV001561241 | uncertain significance | not provided | 2017-10-06 | 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 in zebrafish, yeast and in vitro have shown that this missense change partially disrupts BRF1 protein function (PMID: 25561519). This variant has been reported to segregate with short stature, microcephaly, intellectual disability and characteristic facial dysmorphology in a single family (PMID: 25561519). ClinVar contains an entry for this variant (Variation ID: 161424). This variant is present in population databases (rs373957300, ExAC 0.003%). This sequence change replaces threonine with methionine at codon 259 of the BRF1 protein (p.Thr259Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. |
| Ambry Genetics | RCV002515997 | SCV003708820 | likely pathogenic | Inborn genetic diseases | 2021-04-26 | criteria provided, single submitter | clinical testing | The c.776C>T (p.T259M) alteration is located in coding exon 7 of the BRF1 gene. This alteration results from a C to T substitution at nucleotide position 776, causing the threonine (T) at amino acid position 259 to be replaced by a methionine (M). Based on data from the Genome Aggregation Database (gnomAD) database, the BRF1 c.776C>T alteration was observed in 0.0021% (6/282678) of total alleles studied, with a frequency of 0.012% (3/25070) in the European (Finnish) subpopulation. This alteration was observed to occur in trans with another missense variant in two individuals from one family who presented with clinical features of cerebrofaciodental syndrome including microcephaly, short stature, mild intellectual disability, facial dysmorphism, dental anomalies, scoliosis, delayed bone age, cardiac anomalies, and brain anomalies (Borck, 2015). The p.T259 amino acid is conserved in available vertebrate species. Yeast cells with the p.T259M alteration were observed to decrease promoter binding of Pol III at several tRNA sites and decrease transcription output as compared to yeast with wildtype protein (Borck, 2015). The p.T259M alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. |
| Institute of Human Genetics, |
RCV000150044 | SCV000192005 | pathogenic | Cerebellar-facial-dental syndrome | 2014-12-04 | no assertion criteria provided | research | |
| OMIM | RCV000150044 | SCV000196914 | pathogenic | Cerebellar-facial-dental syndrome | 2015-01-05 | no assertion criteria provided | literature only | |
| Tgen's Center For Rare Childhood Disorders, |
RCV000150044 | SCV001593115 | pathogenic | Cerebellar-facial-dental syndrome | 2021-05-10 | no assertion criteria provided | research | The p.Thr259Met variant was found in a research study in a compound heterozygous state with the variant c.793_794delACinsCATTTA, p.Thr265HisfsX5 (T265HfsX5). The six year old female displayed failure to thrive, microcephaly, dysmorphic facial features, short stature, global developmental delays, anemia, osteopenia, hypotonia, seizures, cerebellar ataxia, sensorineural hearing loss and a bicuspid aortic valve. Bilateral progressive fetal nuclear cataracts with a cortical radial “rider†and numerous vacuoles were also seen. The p.Thr259Met variant was previously described in affected siblings in a compound heterozygous state by Borck et al. (2015). |