ClinVar Miner

Submissions for variant NM_198586.3(NHLRC1):c.468_469del (p.Gly158fs) (rs587776542)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188221 SCV000241828 pathogenic not provided 2015-01-14 criteria provided, single submitter clinical testing c.468_469delAG: p.Gly158ArgfsX17 (G158RfsX17) in exon 1 of the NHLRC1 gene (NM_198586.2). The normal sequence with the bases that are deleted in braces is: ACTC{AG}GGGGA. The c.468_469delAG mutation in the NHLRC1 gene has been reported previously in association with Lafora disease in individuals who had a second NHLRC1 mutation on the opposite allele (Chan et al., 2003; Singh et al., 2008, Turnbull et al., 2008). The deletion causes a frameshift starting with codon Glycine 158, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Gly158ArgfsX17. This mutation is predicted to cause loss of normal protein function through protein truncation, as the last 238 amino acids of the NHLRC1 protein are lost and replaced with 16 incorrect amino acids. Therefore, c.468_469delAG is considered a disease-causing mutation. The variant is found in EPILEPSYV2-1 panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000192029 SCV000461756 pathogenic Lafora disease 2017-04-28 criteria provided, single submitter clinical testing The NHLRC1 c.468_469delAG (p.Gly158ArgfsTer17) variant is a frameshift variant that is predicted to result in premature termination of the protein. This variant is reported as the second most common pathogenic variant in the NHLRC1 gene and the most common deletion (Jansen et al. 2007). This variant has been reported in at least four studies and is found in a total of 21 patients with Lafora type progressive myoclonus epilepsy, including 16 in a homozygous state and five in a compound heterozygous state (Chan et al. 2003; Turnbull et al. 2008; Singh et al. 2008; Lesca et al. 2010). Turnbull et al. (2008) demonstrated a founder effect for the variant in the remote tribal villages of Oman. The p.Gly158ArgfsTer17 variant was absent from 280 controls. It is reported at a frequency of 0.00010 in the African population of the Exome Aggregation Consortium but this is based on one allele in a region of good sequencing coverage so the variant is presumed to be rare. Based on the evidence from the literature and the potential impact of frameshift variants, the p.Gly158ArgfsTer17 variant is classified as pathogenic for Lafora type of progressive myoclonus epilepsy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000192029 SCV000891687 pathogenic Lafora disease 2017-12-30 criteria provided, single submitter clinical testing
Invitae RCV000192029 SCV001374250 pathogenic Lafora disease 2019-09-04 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the NHLRC1 gene (p.Gly158Argfs*17). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 238 amino acids of the NHLRC1 protein. This variant is present in population databases (rs587776542, ExAC 0.01%). This variant has been observed to be homozygous and in combination with another NHLRC1 variant in many individuals affected with Lafora disease (PMID: 12958597, 28556688, 20738377, 18311786, 18263761). ClinVar contains an entry for this variant (Variation ID: 2588). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002706 SCV000022864 pathogenic Epilepsy, progressive myoclonic 2b 2003-10-01 no assertion criteria provided literature only
GeneReviews RCV000192029 SCV000196909 pathogenic Lafora disease 2015-01-22 no assertion criteria provided literature only

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