Submissions for variant NM_018255.4(ELP2):c.1385G>A (p.Arg462Gln)

gnomAD frequency: 0.00002  dbSNP: rs371310428

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001089966	SCV001244968	likely pathogenic	Intellectual disability, autosomal recessive 58	2022-09-02	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_001242875.2(ELP2):c.1580G>A in exon 14 of 23 of the ELP2 gene. This substitution is predicted to create a minor amino acid change from an arginine to a glutamine at position 527 of the protein; NP_001229804.1(ELP2):p.(Arg527Gln). The arginine at this position has high conservation (100 vertebrates, UCSC), and is located within a WD40 repeat (NCBI). In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a global frequency of 0.0016% (4 heterozygotes, 0 homozygotes). This variant has been previously reported as pathogenic in two patients with syndromic global developmental delay (LOVD, Strauss, K. A. et al. (2018)). Different variants in the same codon resulting in a change to a tryptophan and leucine, have also been shown to cause intellectual disability (LOVD, ClinVar, Farwell, K. D. et al. (2015), Najmabadi, H. et al. (2011), Cohen, J. S. et al. (2015)). Based on information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC.
Invitae	RCV002554802	SCV003461795	pathogenic	not provided	2022-08-17	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs371310428, gnomAD 0.01%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ELP2 function (PMID: 33976153). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 870396). This variant is also known as p.R462Q. This missense change has been observed in individual(s) with ELP2-related intellectual disability syndrome (PMID: 32573669, 33393008, 33510603, 33976153, 34653680). 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. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 527 of the ELP2 protein (p.Arg527Gln).
GeneDx	RCV002554802	SCV004035671	pathogenic	not provided	2023-09-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on tRNA-induced acetyl-CoA hydrolysis activity (Kojic et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.1385 G>A p.(R462Q) due to use of alternate nomenclature; This variant is associated with the following publications: (PMID: 34653680, 28726809, 31028937, 32573669, 33393008, 34426522, 33510603, 33961281, 33742171, 36787709, 36360260, 33976153)
Wainwright Lab, University Of Queensland	RCV001310086	SCV001482307	likely pathogenic	Intellectual disability, profound		no assertion criteria provided	clinical testing