ClinVar Miner

Submissions for variant NM_018100.4(EFHC1):c.574G>A (p.Val192Ile)

gnomAD frequency: 0.00009  dbSNP: rs781665913
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187339 SCV000240923 uncertain significance not provided 2015-02-07 criteria provided, single submitter clinical testing p.Val192Ile (GTA>ATA): c.574 G>A in exon 4 of the EFHC1 gene (NM_018100.3). The V192I variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and in silico analysis predicts V192I likely does not alter the protein structure/function. This substitution occurs at a position that is not conserved across species, and Isoleucine is seen at this position in distant evolution. However, other missense mutations have been reported in association with juvenile myoclonic epilepsy, supporting the functional importance of this region of the protein. The variant is found in EPILEPSY panel(s).
Athena Diagnostics RCV000187339 SCV001143854 uncertain significance not provided 2018-12-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003765170 SCV001542430 uncertain significance Absence seizure; Myoclonic epilepsy, juvenile, susceptibility to, 1 2020-09-20 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with EFHC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 205382). This variant is present in population databases (rs781665913, ExAC 0.007%). This sequence change replaces valine with isoleucine at codon 192 of the EFHC1 protein (p.Val192Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine.
Ambry Genetics RCV004020267 SCV004862666 uncertain significance not specified 2023-02-15 criteria provided, single submitter clinical testing The c.574G>A (p.V192I) alteration is located in exon 4 (coding exon 4) of the EFHC1 gene. This alteration results from a G to A substitution at nucleotide position 574, causing the valine (V) at amino acid position 192 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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