ClinVar Miner

Submissions for variant NM_001101426.4(CRPPA):c.532G>A (p.Gly178Arg) (rs202108204)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725038 SCV000333431 uncertain significance not provided 2016-09-21 criteria provided, single submitter clinical testing
GeneDx RCV000725038 SCV000536514 uncertain significance not provided 2017-01-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ISPD gene. The G178R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G178R variant is observed in 20/63016 (0.03%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G178R 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 conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in Human Gene Mutation Database in association with ISPD-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000694888 SCV000823354 uncertain significance Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A7; Muscular dystrophy-dystroglycanopathy (limb-girdle), type c, 7 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 178 of the ISPD protein (p.Gly178Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs202108204, ExAC 0.03%). This variant has not been reported in the literature in individuals with ISPD-related conditions. ClinVar contains an entry for this variant (Variation ID: 282161). 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 disruptive, but 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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