ClinVar Miner

Submissions for variant NM_198586.3(NHLRC1):c.205C>G (p.Pro69Ala) (rs28940576)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188208 SCV000241815 pathogenic not provided 2018-08-15 criteria provided, single submitter clinical testing The P69A variant has been reported in both the homozygous and compound heterozygous state in multiple unrelated patients with Lafora disease (LD) and is considered to be a common pathogenic variant (Chan et al., 2003; Gomez-Abad et al., 2005; Jansen and Andermann, 2015). The P69A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. The P69A variant alters a highly conserved position in the RING domain of the malin protein, and functional studies indicate that it interferes with the protein's ability to interact with other proteins in the glycogen synthesis pathway (Gentry et al., 2005; Solaz-Fuster et al., 2008; Couarch et al., 2011). Therefore, P69A is a considered a pathogenic variant.
Invitae RCV000192026 SCV000551869 pathogenic Lafora disease 2017-12-27 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 69 of the NHLRC1 protein (p.Pro69Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs28940576, ExAC 0.03%). This variant has been reported to be homozygous or compound heterozygous with a pathogenic allele in many individual with Lafora disease (PMID: 12958597, 21505799, 18256682, 19744044, 16529633, 22815132). ClinVar contains an entry for this variant (Variation ID: 2587). Consistent with a loss-of-function mechanism, experimental studies have shown that this missense change impairs the formation of a functional laforin-NHLRC1 protein complex and leads to aberrant glycogen accumulation (PMID: 21505799, 15930137, 18029386). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002705 SCV000022863 pathogenic Epilepsy, progressive myoclonic 2b 2005-03-22 no assertion criteria provided literature only
GeneReviews RCV000192026 SCV000196906 pathogenic Lafora disease 2015-01-22 no assertion criteria provided literature only

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