NM_198586.3:c.436G>A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_198586.3(NHLRC1):c.436G>A(p.Asp146Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000477 in 1,613,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_198586.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NHLRC1 | NM_198586.3 | c.436G>A | p.Asp146Asn | missense_variant | Exon 1 of 1 | ENST00000340650.6 | NP_940988.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152212Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000363 AC: 9AN: 247700Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134540
GnomAD4 exome AF: 0.0000493 AC: 72AN: 1461194Hom.: 0 Cov.: 31 AF XY: 0.0000550 AC XY: 40AN XY: 726914
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74356
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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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 (PMID: 12958597, 21505799, 33773408); 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 (PMID: 21505799, 17952067); In silico analysis indicates 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, 16529633, 21505799, 22047982, 25270369, 25401298, 33773408, 17952067, 12958597, 22425593, 21738631, 27194917, 29431110, 34426522, 16190947, 31589614, 33540374, 31440721, 36964972, 34117373) -
NHLRC1: PM3:Strong, PM2, PM5, PP3, PS3:Supporting -
Lafora disease Pathogenic:1Other:1
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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. -
not specified Pathogenic:1
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Inborn genetic diseases Pathogenic:1
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. -
Myoclonic epilepsy of Lafora 2 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at