rs769301934

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D146E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

NHLRC1
NM_198586.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1O:1

Conservation

PhyloP100: 5.33

Variant links:

Genes affected

NHLRC1 (HGNC:21576): (NHL repeat containing E3 ubiquitin protein ligase 1) The protein encoded by this gene is a single subunit E3 ubiquitin ligase. Laforin is polyubiquitinated by the encoded protein. Defects in this intronless gene lead to an accumulation of laforin and onset of Lafora disease, also known as progressive myoclonic epilepsy type 2 (EPM2).[provided by RefSeq, Mar 2010]

NHLRC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a repeat NHL 1 (size 44) in uniprot entity NHLC1_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_198586.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-18122169-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1524781.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.877

PP5

Variant 6-18122171-C-T is Pathogenic according to our data. Variant chr6-18122171-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162618.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, Uncertain_significance=1, not_provided=1, Likely_pathogenic=1}. Variant chr6-18122171-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHLRC1	NM_198586.3 linkuse as main transcript	c.436G>A	p.Asp146Asn	missense_variant	1/1	ENST00000340650.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHLRC1	ENST00000340650.6 linkuse as main transcript	c.436G>A	p.Asp146Asn	missense_variant	1/1		NM_198586.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000363

AC:

AN:

247700

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134540

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000628

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000493

AC:

AN:

1461194

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

726914

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000567

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	NHLRC1: PM3:Strong, PM2, PM5, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2023	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) -

Lafora disease

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	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 provided, no classification provided	literature only	GeneReviews	-	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2020

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. -

Epilepsy, progressive myoclonic, 2b

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 26, 2024

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.24

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

-0.072

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.62

REVEL

Uncertain

0.40

Sift

Benign

0.29

Sift4G

Benign

0.17

Polyphen

1.0

Vest4

0.75

MutPred

0.80

Gain of MoRF binding (P = 0.0493);

MVP

0.95

MPC

1.0

ClinPred

0.45

GERP RS

5.2

Varity_R

0.16

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over