rs28940576
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_198586.3(NHLRC1):c.205C>G(p.Pro69Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000123 in 1,584,602 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 Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. P69P) has been classified as Likely benign.
Frequency
Consequence
NM_198586.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NHLRC1 | NM_198586.3 | c.205C>G | p.Pro69Ala | missense_variant | 1/1 | ENST00000340650.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NHLRC1 | ENST00000340650.6 | c.205C>G | p.Pro69Ala | missense_variant | 1/1 | NM_198586.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152244Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000112 AC: 22AN: 196976Hom.: 0 AF XY: 0.0000909 AC XY: 10AN XY: 109964
GnomAD4 exome AF: 0.000128 AC: 183AN: 1432358Hom.: 0 Cov.: 35 AF XY: 0.000125 AC XY: 89AN XY: 711884
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152244Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74376
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 15, 2018 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 22, 2020 | The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. - |
Lafora disease Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 69 of the NHLRC1 protein (p.Pro69Ala). This variant is present in population databases (rs28940576, gnomAD 0.02%). This missense change has been observed in individuals with Lafora disease (PMID: 12958597, 16529633, 18256682, 19744044, 21505799, 22815132). ClinVar contains an entry for this variant (Variation ID: 2587). 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) performed at Invitae indicates that this missense variant is expected to disrupt NHLRC1 protein function. Experimental studies have shown that this missense change affects NHLRC1 function (PMID: 15930137, 18029386, 21505799). For these reasons, this variant has been classified as Pathogenic. - |
Epilepsy, progressive myoclonic, 2b Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 22, 2005 | - - |
NHLRC1-related condition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 20, 2023 | The NHLRC1 c.205C>G variant is predicted to result in the amino acid substitution p.Pro69Ala. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with Lafora disease (Chan et al. 2003. PubMed ID: 12958597; Franceschetti et al. 2006. PubMed ID: 16529633; RomΓ‘-Mateo et al. 2012. PubMed ID: 22815132). Functional studies showed this variant is detrimental and leads to intracellular glycogen accumulation (Gentry et al. 2005. PubMed ID: 15930137; Couarch et al. 2011. PubMed ID: 21505799). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at