ClinVar Genomic variation as it relates to human health

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31127727, 29620724, 28454995)

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 169 of the EFEMP2 protein (p.Arg169His). This variant is present in population databases (rs141310608, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of EFEMP2-related conditions (PMID: 28454995, 29620724, 31127727). ClinVar contains an entry for this variant (Variation ID: 472828). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.

EFEMP2 NM_016938.5 exon 6 p.Arg169His (c.506G>A): This variant has been reported in the literature in one individual with features of a skeletal dysplasia, as well as reported as homozygous in one individual with an unspecified muscle disease (Alfares 2017 PMID:28454995, Maddirevula 2018 PMID:29620724). This variant is also present in 0.01% (23/128572) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-65637693-C-T) and is present in ClinVar (Variation ID:472828). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

The p.R169H variant (also known as c.506G>A), located in coding exon 5 of the EFEMP2 gene, results from a G to A substitution at nucleotide position 506. The arginine at codon 169 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a homozygous state in a subject with muscle weakness (Alfares A et al. Mol. Genet. Metab., 2017 06;121:91-95). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Variant summary: EFEMP2 c.506G>A (p.Arg169His) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of 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 9.6e-05 in 250720 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in EFEMP2 causing Autosomal Recessive Cutis Laxa (9.6e-05 vs 0.00071), allowing no conclusion about variant significance. c.506G>A has been reported in the literature in homozygous individuals affected with features of Autosomal Recessive Cutis Laxa and/or with features of musculoskeletal disorders (Alfares_2017, Maddirevula_2018, Westra_2019). These reports do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Cutis Laxa. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28454995, 29620724, 31127727). ClinVar contains an entry for this variant (Variation ID: 472828). Based on the evidence outlined above, the variant was classified as uncertain significance.

The EFEMP2 c.506G>A variant is predicted to result in the amino acid substitution p.Arg169His. This variant was reported in the homozygous state individuals with connective tissue disorder, scoliosis, joint dislocations, contractures and muscle disorder (Alfares et al. 2017. PubMed ID: 28454995; Maddirevula et al. 2018. PubMed ID: 29620724; Westra et al. 2019. PubMed ID: 31127727). In at least two cases, parents were from a consanguineous marriage. Functionnal characterization was not preformed. This variant is reported in 0.018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-65637693-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.