ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.1108G>A (p.Asp370Asn) (rs200007067)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236775 SCV000292587 uncertain significance not provided 2018-04-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the IGHMBP2 gene. The D370N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to ourknowledge. This variant is observed in 39/126650 (0.03%) alleles from individuals of Europeanbackground in large population cohorts (Lek et al., 2016). The D370N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in someproperties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues have been reported in the Human GeneMutation Database in individuals with IGHMBP2-related disorders (Stenson et al., 2014). Therefore,based on the currently available information, it is unclear whether this variant is a pathogenic variantor a rare benign variant.
Invitae RCV000533172 SCV000642297 uncertain significance Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2018-04-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 370 of the IGHMBP2 protein (p.Asp370Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs200007067, ExAC 0.05%) but has not been reported in the literature in individuals with an IGHMBP2-related disease. ClinVar contains an entry for this variant (Variation ID: 245628). 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, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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