ClinVar Miner

Submissions for variant NM_016938.5(EFEMP2):c.506G>A (p.Arg169His)

gnomAD frequency: 0.00006  dbSNP: rs141310608
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000556089 SCV000652067 uncertain significance Cutis laxa, autosomal recessive, type 1B 2022-07-30 criteria provided, single submitter clinical testing 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000556089 SCV001468373 uncertain significance Cutis laxa, autosomal recessive, type 1B 2021-03-30 criteria provided, single submitter clinical testing 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.
GeneDx RCV001591263 SCV001824520 uncertain significance not provided 2020-10-19 criteria provided, single submitter clinical testing 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)
Ambry Genetics RCV002341433 SCV002643602 uncertain significance Cardiovascular phenotype 2022-07-21 criteria provided, single submitter clinical testing 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.
Fulgent Genetics, Fulgent Genetics RCV000556089 SCV002807011 uncertain significance Cutis laxa, autosomal recessive, type 1B 2022-02-16 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003980005 SCV004788199 uncertain significance EFEMP2-related disorder 2023-11-10 criteria provided, single submitter clinical testing 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.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City RCV000556089 SCV001133191 likely pathogenic Cutis laxa, autosomal recessive, type 1B 2019-09-26 no assertion criteria provided clinical testing

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