Submissions for variant NM_001378120.1(MBD5):c.2840G>A (p.Gly947Glu)

gnomAD frequency: 0.00007  dbSNP: rs114359726

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724094	SCV000225045	uncertain significance	not provided	2014-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000724094	SCV000241709	uncertain significance	not provided	2014-10-16	criteria provided, single submitter	clinical testing	p.G947E(GGA>GAA):c.2840G>A in exon 10 of the MBD5 gene (NM_018328.4) The G947E variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It was identified on 1/167 (.59%) control alleles in individuals of European ancestry in the 1000 Genomes database. The G947E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is highly conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, only deletions and frameshift mutations in MBD5 have been published in association with epilepsy. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CHILD-EPI,EPILEPSY panel(s).
Fulgent Genetics, Fulgent Genetics	RCV000515360	SCV000611480	uncertain significance	Intellectual disability, autosomal dominant 1	2017-05-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000515360	SCV003249973	uncertain significance	Intellectual disability, autosomal dominant 1	2024-09-22	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 947 of the MBD5 protein (p.Gly947Glu). This variant is present in population databases (rs114359726, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MBD5-related conditions. ClinVar contains an entry for this variant (Variation ID: 193727). 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) indicates that this missense variant is not expected to disrupt MBD5 protein function with a negative predictive value of 80%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782283	SCV005395873	uncertain significance	not specified	2024-09-16	criteria provided, single submitter	clinical testing	Variant summary: MBD5 c.2840G>A (p.Gly947Glu) results in a non-conservative amino acid change in 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 3.6e-05 in 249184 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2840G>A in individuals affected with MBD5 Associated Neurodevelopmental Disorder and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 193727). Based on the evidence outlined above, the variant was classified as uncertain significance.