ClinVar Miner

Submissions for variant NM_198586.3(NHLRC1):c.436G>A (p.Asp146Asn) (rs769301934)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188209 SCV000241816 pathogenic not provided 2017-02-17 criteria provided, single submitter clinical testing The D146N variant in the NHLRC1 gene has been reported multiple times previously, in both the homozygous and compound heterozygous state, in individuals with Lafora disease (LD) (Chan et al., 2003; Franceschetti et al., 2006; Couarch et al., 2011; Ferlazzo et al., 2014). Functional studies indicate that D146N interferes with the protein's ability to interact with other proteins in the glycogen synthesis pathway (Couarch et al., 2011). The D146N variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D146N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Therefore, the D146N variant is classified as a pathogenic variant.
Invitae RCV000192027 SCV000836188 pathogenic Lafora disease 2018-05-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 146 of the NHLRC1 protein (p.Asp146Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs769301934, ExAC 0.009%). This variant has been reported in multiple individuals with Lafora disease as  homozygous or as compound heterozygous segregating with disease in several families (PMID: 12958597, 16529633, 22047982, 25667860, 21505799). ClinVar contains an entry for this variant (Variation ID: 162618). Experimental studies have shown that this missense change [p.Asp146Asn] disrupts laforin-malin complex interaction and fails to supress glycogen synthase leading to glycogen accumulation and formation of Lafora bodies (PMID: 21505799, 17952067). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000188209 SCV001246050 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV001169931 SCV001251661 uncertain significance not specified 2020-05-03 criteria provided, single submitter clinical testing
GeneReviews RCV000192027 SCV000196907 pathogenic Lafora disease 2015-01-22 no assertion criteria provided literature only

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