ClinVar Miner

Submissions for variant NM_016938.5(EFEMP2):c.554G>A (p.Arg185His)

gnomAD frequency: 0.00002  dbSNP: rs143662598
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000801175 SCV000940941 uncertain significance Cutis laxa, autosomal recessive, type 1B 2022-06-22 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 185 of the EFEMP2 protein (p.Arg185His). This variant is present in population databases (rs143662598, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with EFEMP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 646814). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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.
GeneDx RCV001766659 SCV001991384 uncertain significance not provided 2023-09-22 criteria provided, single submitter clinical testing Has been previously reported with the ANKRD1 T116M variant in 1/34 patients with sudden unexplained death (Neubauer et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33895855, 29350269)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000801175 SCV004565089 uncertain significance Cutis laxa, autosomal recessive, type 1B 2023-05-01 criteria provided, single submitter clinical testing The EFEMP2 c.554G>A; p.Arg185His (rs143662598) is reported in the literature in one individual affected with sudden unexplained death (Neubauer 2018, Neubauer 2021). This variant is also reported in ClinVar (Variation ID: 646814) and is found in the general population with an overall frequency of 0.004% (10/282072 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.374). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Neubauer J et al. Exome analysis in 34 sudden unexplained death (SUD) victims mainly identified variants in channelopathy-associated genes. Int J Legal Med. 2018 Jul;132(4):1057-1065. PMID: 29350269. Neubauer J et al. Re-evaluation of single nucleotide variants and identification of structural variants in a cohort of 45 sudden unexplained death cases. Int J Legal Med. 2021 Jul;135(4):1341-1349. PMID: 33895855.

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