ClinVar Miner

Submissions for variant NM_018100.4(EFHC1):c.1547T>C (p.Met516Thr)

gnomAD frequency: 0.00001  dbSNP: rs372520849
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187371 SCV000240956 uncertain significance not provided 2015-08-10 criteria provided, single submitter clinical testing p.Met516Thr (ATG>ACG): c.1547 T>C in exon 9 of the EFHC1 gene (NM_018100.3). The Met516Thr missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Met516Thr in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a non-polar Methionine residue is replaced by a polar Threonine residue. It alters a poorly conserved position in the DM10 domain of the protein. Some in silico algorithms predict Met516Thr may be damaging to protein structure/function, although another model suggests it may be benign. Therefore, based on the currently available information, it is unclear whether Met516Thr is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV003765187 SCV001229182 uncertain significance Absence seizure; Myoclonic epilepsy, juvenile, susceptibility to, 1 2022-07-12 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 516 of the EFHC1 protein (p.Met516Thr). This variant is present in population databases (rs372520849, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with EFHC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 205413). 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 C0"). 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.

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