ClinVar Miner

Submissions for variant NM_198586.3(NHLRC1):c.468del (p.Gly158fs) (rs757954108)

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Total submissions: 2
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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 2019-06-05 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the NHLRC1 gene (p.Gly158Glufs*74). 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 (rs757954108, ExAC 0.009%). This variant has been observed in combination with another NHLRC1 variant in an individual affected with progressive myoclonic epilepsy or Lafora disease (PMID: 12958597, 15781812). ClinVar contains an entry for this variant (Variation ID: 280034). This variant disrupts the C-terminus of the NHLRC1 protein. Other variant(s) that disrupt this region (Ser300Valfs*13) have been determined to be pathogenic (PMID: 16021330). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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