ClinVar Miner

Submissions for variant NM_198586.3(NHLRC1):c.386C>A (p.Pro129His) (rs750465793)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188211 SCV000241818 pathogenic not provided 2015-01-02 criteria provided, single submitter clinical testing p.Pro129His (CCC>CAC): c.386 C>A in exon 1 of the NHLRC1 gene (NM_198586.2) The P129H missense change in the NHLRC1 gene has been reported previously as a homozygous mutation in an individual with Lafora disease (Lohi et al., 2007). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. P129H 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. It alters a highly conserved position predicted to be within the first NHL domain of the protein, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, P129H is considered a published, disease-causing mutation. The variant is found in EPILEPSYV2-1 panel(s).
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000602467 SCV000743887 pathogenic Lafora disease 2014-10-08 criteria provided, single submitter clinical testing
Invitae RCV000602467 SCV000759835 pathogenic Lafora disease 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 129 of the NHLRC1 protein (p.Pro129His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is present in population databases (rs750465793, ExAC 0.002%). This variant has been observed to be homozygous or in combination with another NHLRC1 variant in individuals affected with progressive myoclonic epilepsy (PMID: 20738377, 29588937, 30701169). ClinVar contains an entry for this variant (Variation ID: 206187). 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. For these reasons, this variant has been classified as Pathogenic.
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000602467 SCV000734491 pathogenic Lafora disease no assertion criteria provided clinical testing

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