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

gnomAD frequency: 0.00004  dbSNP: rs587776542

Total submissions: 7

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 Laboratory Services, 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, Sultan Qaboos University	RCV000192029	SCV000891687	pathogenic	Lafora disease	2017-12-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000192029	SCV001374250	pathogenic	Lafora disease	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly158Argfs*17) in the NHLRC1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 238 amino acid(s) of the NHLRC1 protein. This variant is present in population databases (rs587776542, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Lafora disease (PMID: 12958597, 18263761, 18311786, 20738377, 28556688). ClinVar contains an entry for this variant (Variation ID: 2588). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002326660	SCV002634488	pathogenic	Inborn genetic diseases	2017-07-25	criteria provided, single submitter	clinical testing	The c.468_469delAG variant, located in coding exon 1 of the NHLRC1 gene, results from a deletion of two nucleotides at nucleotide positions 468 to 469, causing a translational frameshift with a predicted alternate stop codon (p.G158Rfs*17). This mutation is one of the most commonly reported NHLRC1 mutations and has been detected in several individuals with biopsy confirmed Lafora disease in both the homozygous and compound heterozygous states (Singh S et al. Hum. Mutat., 2008 Jun;29:E1-12; Chan EM et al. Nat. Genet., 2003 Oct;35:125-7; Kecmanovi M et al. Clin. Genet., 2016 Jan;89:104-8; Lesca G et al. Epilepsia, 2010 Sep;51:1691-8). In addition to the clinical data presented in the lieterature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000002706	SCV000022864	pathogenic	Myoclonic epilepsy of Lafora 2	2003-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000192029	SCV000196909	not provided	Lafora disease		no assertion provided	literature only