ClinVar Miner

Submissions for variant NM_182961.4(SYNE1):c.16371A>C (p.Gln5457His)

gnomAD frequency: 0.00002  dbSNP: rs370002959
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489395 SCV000576658 uncertain significance not provided 2017-04-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SYNE1 gene. The Q5386H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Q5386H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Q5386H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001851308 SCV002282344 uncertain significance Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant 2021-08-30 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 5386 of the SYNE1 protein (p.Gln5386His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs370002959, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 426261). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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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