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

gnomAD frequency: 0.00006  dbSNP: rs757954108

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000368630	SCV000329768	pathogenic	not provided	2016-03-28	criteria provided, single submitter	clinical testing	The c.468delA pathogenic variant in the NHLRC1 gene has been reported previously in an individual with Lafora disease who was compound heterozygous for c.468delA and a second NHLRC1 pathogenic variant (Chan et al., 2003). The deletion causes a frameshift starting with codon Glycine 158, changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 74 of the new reading frame, denoted p.Gly158GlufsX74. This pathogenic variant is predicted to cause loss of normal protein function through protein truncation as the last 238 amino acid residues are replaced with 73 incorrect amino acid residues. Therefore, c.468delA is considered a pathogenic variant.
Invitae	RCV001202002	SCV001373098	pathogenic	Lafora disease	2022-07-12	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs757954108, gnomAD 0.02%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the NHLRC1 protein in which other variant(s) (p.Ser300Valfs*13) have been determined to be pathogenic (PMID: 16021330). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 280034). This premature translational stop signal has been observed in individual(s) with progressive myoclonic epilepsy (PMID: 15781812). This sequence change creates a premature translational stop signal (p.Gly158Glufs*74) 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.
CeGaT Center for Human Genetics Tuebingen	RCV000368630	SCV004163135	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	NHLRC1: PVS1, PM2