ClinVar Miner

Submissions for variant NM_004667.6(HERC2):c.11716C>T (p.Arg3906Cys)

gnomAD frequency: 0.00001  dbSNP: rs770688775
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000421606 SCV000536406 uncertain significance not provided 2022-06-03 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
New York Genome Center RCV001782906 SCV002025667 uncertain significance Developmental delay with autism spectrum disorder and gait instability 2020-04-28 criteria provided, single submitter clinical testing The inherited p.Arg3906Cys in the HERC2 gene has not been reported in the literature in individuals with neurological disorders. The variant has 0.00006771 allele frequency (17 out of 251,080 heterozygous alleles) in the gnomAD database indicating it is a rare allele in the general population. The variant affects moderately conserved residues. In silico prediction tools provide conflicting interpretations about the variants potential deleterious effects on normal protein function. Based on the available evidence, the inherited p.Arg3906Cys varaint in the HERC2 gene is assessed as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000421606 SCV004272592 uncertain significance not provided 2024-10-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3906 of the HERC2 protein (p.Arg3906Cys). This variant is present in population databases (rs770688775, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with HERC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 393051). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt HERC2 protein function with a negative predictive value of 80%. 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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