ClinVar Miner

Submissions for variant NM_001540.5(HSPB1):c.277G>A (p.Asp93Asn) (rs777201941)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498200 SCV000590274 uncertain significance not provided 2017-06-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the HSPB1 gene. The D93N variant has been reported previously as a variant of unknown significance in association with CMT; however, additional clinical information and inheritance pattern were not provided (DiVincenzo et al., 2014). The D93N variant is observed in 3/5180 (0.06%) alleles from individuals of European non-Finnish background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D93N 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 where amino acids with similar properties to Aspartic acid are tolerated across species. In silico analysis predicts this variant is probably 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 RCV000544986 SCV000640208 uncertain significance Charcot-Marie-Tooth disease type 2F 2018-03-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 93 of the HSPB1 protein (p.Asp93Asn). 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 (rs777201941, ExAC 0.06%). This variant was reported in an individual who underwent testing for Charcot-Marie-Tooth disease (PMID: 25614874). ClinVar contains an entry for this variant (Variation ID: 432537). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; 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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