Submissions for variant NM_001375380.1(EBF3):c.934C>T (p.Arg312Ter)

dbSNP: rs1064796669

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484995	SCV000573615	pathogenic	not provided	2023-06-17	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect with mislocalization of the truncated EBF3 protein and significantly reduced transcriptional activation of a reporter gene (PMID: 28017373); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28017373, 36937983)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001267692	SCV001445941	pathogenic	Hypotonia, ataxia, and delayed development syndrome	2020-06-03	criteria provided, single submitter	curation	The heterozygous p.Arg303Ter variant in EBF3 was identified by our study in 1 individual with hypotonia, ataxia, and delayed development syndrome. Trio genome analysis showed this variant to be de novo. The p.Arg303Ter variant has also been reported in 1 individual of unknown ethnicity with hypotonia, ataxia, and delayed development syndrome (PMID: 28017373), and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 423864) as pathogenic by GeneDx. In vitro functional studies provide some evidence that the variant may slightly impact protein function (PMID: 28017373). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 303, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the EBF3 gene is strongly associated with hypotonia, ataxia, and delayed development syndrome. In summary, this variant meets criteria to be classified as pathogenic for hypotonia, ataxia, and delayed development syndrome in an autosomal dominant manner based on multiple de novo occurrences in affected individuals, absence of the variant from control populations, and the predicted LOF mechanism for this variant. ACMG/AMP Criteria applied: PS2, PM2, PVS1_strong, PS3_supporting , PS4_supporting (Richards 2015).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000484995	SCV001480121	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001267692	SCV002022160	pathogenic	Hypotonia, ataxia, and delayed development syndrome	2019-07-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003302716	SCV004007527	pathogenic	Inborn genetic diseases	2023-05-17	criteria provided, single submitter	clinical testing	The c.907C>T (p.R303*) alteration, located in coding exon 10 of the EBF3 gene, consists of a C to T substitution at nucleotide position 907. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 303. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported de novo in multiple individuals with features consistent with EBF3-related neurodevelopmental disorder (Harms, 2017; van der Veen, 2018). Based on the available evidence, this alteration is classified as pathogenic.