ClinVar Genomic variation as it relates to human health

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: 27412952, 27159321, 28939701, 27350610, 26395190, 25473036, 25058219, 25604853, 27843092, 28844315, 29071585, 29671881, 31506229, 31568715, 32746448)

The p.Asn238Ser variant in RMND1 has been reported in the homozygous or compound heterozygous state in at least 10 individuals with combined oxidative phosphory lation deficiency (Taylor 2014, Janer 2015, Vanderver 2016, Ng 2016, Gupta 2016, Ulrick 2017). In vitro functional studies provide some evidence that the p.Asn2 38Ser variant may impact protein function (Janer 2015); however, these types of assays may not accurately represent biological function. This variant has been i dentified in 0.03% (44/126078) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144972972). Althoug h this variant has been seen in the general population, its frequency is low eno ugh to be consistent with a recessive carrier frequency. In summary, this varian t meets criteria to be classified as pathogenic for combined oxidative phosphory lation deficiency in an autosomal recessive manner based upon presence in affect ed individuals, frequency in controls, and functional evidence. ACMG/AMP Criteri a applied: PM3_VeryStrong; PM2_Supporting; PS3_Supporting

Variant summary: RMND1 c.713A>G (p.Asn238Ser) results in a conservative amino acid change located in the Domain of unknown function DUF155 (IPR003734) of 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 0.0002 in 249272 control chromosomes. This frequency does not allow conclusions about variant significance. c.713A>G has been reported in the literature in multiple individuals affected with features of Combined Oxidative Phosphorylation Defect Type 11 ranging from muscle defects, seizures, deafness, and renal tubular acidosis (example, Broenen_2019, Janer_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 238 of the RMND1 protein (p.Asn238Ser). This variant is present in population databases (rs144972972, gnomAD 0.03%). This missense change has been observed in individual(s) with combined oxidative phosphorylation deficiency 11 (PMID: 25604853, 26395190, 31506229, 31568715). 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: 225255). 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 RMND1 protein function. Experimental studies have shown that this missense change affects RMND1 function (PMID: 25604853). For these reasons, this variant has been classified as Pathogenic.

The c.713A>G (p.N238S) alteration is located in exon 5 (coding exon 4) of the RMND1 gene. This alteration results from an A to G substitution at nucleotide position 713, causing the asparagine (N) at amino acid position 238 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of 0.02% (54/280666) total alleles studied. The highest observed frequency was 0.04% (47/128420) of European (non-Finnish) alleles. This alteration was detected in the homozygous state and in conjunction with another alteration in RMND1 in multiple individuals with RMND1-related combined oxidative phosphorylation deficiency (Taylor, 2014; Janer, 2015; Ng, 2016; Gupta, 2016; Vanderver, 2016; Ravn, 2016; van Dieman, 2017; Ulrick, 2017; Demain, 2018; Shayoto, 2019; Broenen, 2019). Experimental studies show that this alteration leads to reduced RMND1 activity in patient-derived cells (Janer, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

This patient is heterozygous for a known pathogenic variant, c.713A>G (p.Asn238Ser), in the RMND1 gene. This variant has been previously reported in conjunction with a second pathogenic variant in a patient with epileptic encephalopathy and lactic acidosis. Functional studies have shown that this variant causes a decrease in the level of RMND1 protein (Janer et al 2015: European Journal of Human Genetics, 1-7). This variant is therefore considered to be pathogenic.