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

gnomAD frequency: 0.00003  dbSNP: rs769301934

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188209	SCV000241816	pathogenic	not provided	2023-01-09	criteria provided, single submitter	clinical testing	Observed multiple times with another NHLRC1 variant in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Chan et al., 2003; Couarch et al., 2011; Riva et al., 2021); Published functional studies indicate that D146N interferes with the protein's ability to clear glycogen accumulation and to interact with other proteins in the glycogen synthesis pathway (Vilchez et al., 17952067; Couarch et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18029386, 25667860, 22425593, 25401298, 17952067, 25270369, 22047982, 21738631, 21505799, 27194917, 16529633, 29431110, 34426522, 16190947, 31589614, 33540374, 34117373, 33773408, 12958597)
Invitae	RCV000192027	SCV000836188	pathogenic	Lafora disease	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 146 of the NHLRC1 protein (p.Asp146Asn). This variant is present in population databases (rs769301934, gnomAD 0.01%). This missense change has been observed in individual(s) with Lafora disease (PMID: 12958597, 16529633, 21505799, 22047982, 25667860). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162618). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NHLRC1 protein function. Experimental studies have shown that this missense change affects NHLRC1 function (PMID: 17952067, 21505799). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000188209	SCV001246050	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	NHLRC1: PM3:Strong, PM2, PM5, PP3, PS3:Supporting
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV001169931	SCV001251661	uncertain significance	not specified	2020-05-03	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000188209	SCV001762207	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326860	SCV002627617	pathogenic	Inborn genetic diseases	2020-03-04	criteria provided, single submitter	clinical testing	The p.D146N pathogenic mutation (also known as c.436G>A), located in coding exon 1 of the NHLRC1 gene, results from a G to A substitution at nucleotide position 436. The aspartic acid at codon 146 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been detected in both the homozygous and compound heterozygous states in individuals with Lafora disease who experienced later than average disease onset and atypically slow disease progression (Chan EM et al. Nat. Genet., 2003 Oct;35:125-7; Baykan B et al. Epilepsia, 2005 Oct;46:1695-7; Franceschetti S et al. Epilepsia, 2006 Mar;47:640-3; Salar S et al. Epilepsy Res., 2012 Feb;98:273-6; Ferlazzo E et al. Epilepsia, 2014 Dec;55:e129-33; Lanoiselée HM et al. Epilepsy Behav Case Rep, 2014 Jan;2:19-21; Bisulli F et al. Orphanet J Rare Dis, 2019 06;14:149). In addition, in two functional studies, this alteration was shown to impair interaction with laforin and failed to induce the degradation of protein targeting to glycogen (PTG), leading to intracellular glycogen accumulation (Couarch P et al. J. Mol. Med., 2011 Sep;89:915-25; Vilchez D et al. Nat. Neurosci., 2007 Nov;10:1407-13). Of note, these results are consistent with a finding in the malin knockout mouse, which showed glycogen accumulation underlies neurodegeration in Lafora disease (Duran J et al. Hum. Mol. Genet., 2014 Jun;23:3147-56). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneReviews	RCV000192027	SCV000196907	not provided	Lafora disease		no assertion provided	literature only