ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.3220G>A (p.Asp1074Asn) (rs751514645)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188911 SCV000242541 uncertain significance not specified 2017-10-05 criteria provided, single submitter clinical testing The D1074N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D1074N variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The D1074N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved and is predicted to be within the cytoplasmic loop between the second and third homologous domains. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001229261 SCV001401701 uncertain significance Early infantile epileptic encephalopathy 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1074 of the SCN1A protein (p.Asp1074Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs751514645, ExAC 0.002%). This variant has not been reported in the literature in individuals with SCN1A-related disease. ClinVar contains an entry for this variant (Variation ID: 206797). This variant identified in the SCN1A gene is located in the cytoplasmic interdomain linker D2-D3 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine 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. 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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