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

gnomAD frequency: 0.00001  dbSNP: rs750465793

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188211	SCV000241818	likely pathogenic	not provided	2022-02-24	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect resulting in impaired mitochondrial function, increased oxidative stress, and reduced antioxidant enzymatic activity (Rom-Mateo et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32587944, 17389303, 30701169, 29588937, 19267391, 24838580, 20738377)
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000602467	SCV000743887	pathogenic	Lafora disease	2014-10-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000602467	SCV000759835	pathogenic	Lafora disease	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 129 of the NHLRC1 protein (p.Pro129His). This variant is present in population databases (rs750465793, gnomAD 0.002%). This missense change has been observed in individual(s) with progressive myoclonic epilepsy (PMID: 20738377, 29588937, 30701169). ClinVar contains an entry for this variant (Variation ID: 206187). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NHLRC1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800326	SCV005423467	pathogenic	Myoclonic epilepsy of Lafora 2	2024-10-03	criteria provided, single submitter	clinical testing	Variant summary: NHLRC1 c.386C>A (p.Pro129His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 244298 control chromosomes. c.386C>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Myoclonic Epilepsy Of Lafora 2 (Lohi_2007, Zutt_2016, Lesca_2010, Nicolescu_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20738377, 17389303, 30701169, 29588937). ClinVar contains an entry for this variant (Variation ID: 206187). Based on the evidence outlined above, the variant was classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000602467	SCV000734491	pathogenic	Lafora disease		no assertion criteria provided	clinical testing