ClinVar Miner

Submissions for variant NM_005334.3(HCFC1):c.3892G>A (p.Glu1298Lys) (rs781949446)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522865 SCV000618700 uncertain significance not provided 2017-07-03 criteria provided, single submitter clinical testing The E1298K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E1298K variant is observed in 1/9303 (0.01%) alleles from individuals of Latino background, including 1 hemizygous individual in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E1298K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001314423 SCV001504957 uncertain significance Mental retardation 3, X-linked 2020-10-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1298 of the HCFC1 protein (p.Glu1298Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs781949446, ExAC 0.01%). This variant has not been reported in the literature in individuals with HCFC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 450155). 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: Tolerated; PolyPhen-2: Probably Damaging; 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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