ClinVar Miner

Submissions for variant NM_001101426.4(CRPPA):c.79A>C (p.Thr27Pro) (rs558064127)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000173205 SCV000224300 benign not specified 2016-08-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000292121 SCV000468024 uncertain significance Congenital Muscular Dystrophy, alpha-dystroglycan related 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000173205 SCV000490568 uncertain significance not specified 2016-12-08 criteria provided, single submitter clinical testing The T27P variant in the ISPD gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T27P variant was not observed in approximately 3,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T27P 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. However, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. We interpret T27P as a variant of uncertain significance.
Invitae RCV000531834 SCV000652589 uncertain significance Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A7; Muscular dystrophy-dystroglycanopathy (limb-girdle), type c, 7 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 27 of the ISPD protein (p.Thr27Pro). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and proline. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in the compound heterozygous state in an individual affected with muscular dystophy (PMID: 29382405). ClinVar contains an entry for this variant (Variation ID: 193158). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on ISPD function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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