Submissions for variant NM_018255.4(ELP2):c.617A>G (p.His206Arg)

gnomAD frequency: 0.00001  dbSNP: rs773432002

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000210560	SCV000262876	pathogenic	Inborn genetic diseases	2013-09-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000498075	SCV000589770	likely pathogenic	not provided	2017-06-07	criteria provided, single submitter	clinical testing	The H271R variant in the ELP2 gene has been reported previously in trans with another ELP2 variant in brothers with intellectual disability (Cohen et al., 2015). The H271R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The H271R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The H271R variant is reported as pathogenic in ClinVar but additional evidence is not available (ClinVar SCV000262876.2; Landrum et al., 2016]. We interpret H271R as a likely pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000415587	SCV002500442	likely pathogenic	Intellectual disability, autosomal recessive 58	2022-03-17	criteria provided, single submitter	clinical testing	Variant summary: ELP2 c.617A>G (p.His206Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251380 control chromosomes (gnomAD). c.617A>G has been reported in the literature in compound heterozygous individuals affected with severe intellectual disability and neurodevelopmental delay (Cohen_2015, Kojic_2021) with strong co-segregation within a family where unaffected family members were either carriers for one ELP2 variant or non-carriers (Cohen_2015). These data indicate that the variant is likely to be associated with disease. One publication showed that the variant does not impact protein stability or Elongator protein complex formation, but significantly reduces tRNA induced acetyl COA hydroxylase activity (~60% activity, Kojic_2021). Mice homozygous for the same conserved amino acid residue have developmental delay and microcephaly, with reduction in cortical thickness, decrease in the number of interneurons, and significant changes in brain connectivity (Kojic_2021). Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM	RCV000415587	SCV000493999	pathogenic	Intellectual disability, autosomal recessive 58	2022-02-18	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000509137	SCV000607244	not provided	ELP2-related disorder		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.