rs28940576

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP2PP3_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 (★★). Synonymous variant affecting the same amino acid position (i.e. P69P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

NHLRC1
NM_198586.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 6.56

Publications

24 publications found

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 Gene-Disease associations (from GenCC):

Lafora disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics

NHLRC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.49521 (below the threshold of 3.09). Trascript score misZ: -0.085446 (below the threshold of 3.09). GenCC associations: The gene is linked to Lafora disease.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

PP5

Variant 6-18122402-G-C is Pathogenic according to our data. Variant chr6-18122402-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHLRC1	NM_198586.3 link	c.205C>G	p.Pro69Ala	missense_variant	Exon 1 of 1	ENST00000340650.6	NP_940988.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHLRC1	ENST00000340650.6 link	c.205C>G	p.Pro69Ala	missense_variant	Exon 1 of 1	6	NM_198586.3	ENSP00000345464.3

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000112

AC:

AN:

196976

AF XY:

0.0000909

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000130

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000209

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000128

AC:

183

AN:

1432358

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

711884

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33244

American (AMR)

AF:

0.000119

AC:

AN:

41996

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25800

East Asian (EAS)

AF:

0.00

AC:

AN:

39230

South Asian (SAS)

AF:

0.00

AC:

AN:

85134

European-Finnish (FIN)

AF:

0.0000274

AC:

AN:

36514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5096

European-Non Finnish (NFE)

AF:

0.000156

AC:

172

AN:

1105666

Other (OTH)

AF:

0.0000670

AC:

AN:

59678

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41472

American (AMR)

AF:

0.0000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000522

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Myoclonic epilepsy of Lafora 2

Pathogenic:2

Mar 22, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 21, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Pathogenic:2

Jan 22, 2020

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 12, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Affects the RING finger domain and reported as the most common pathogenic variant observed in the NHLRC1 gene (PMID: 16311711); Published functional studies of P69A demonstrate impairment of malin's interaction with laforin resulting in abnormal accumulation of intracellular glycogen (PMID: 15930137, 18029386, 21505799); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21505799, 28556688, 18029386, 15930137, 12958597, 20738377, 16134145, 19744044, 18256682, 15781812, 16529633, 20301563, 29431110, 33773408, 31589614, 31440721, 31758957, 31858178, 25270369, 31227012, 36638890, 33368637, 16311711, 35184210, 36210672) -

Lafora disease

Pathogenic:1Other:1

Sep 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NHLRC1 protein function with a positive predictive value of 80%. 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. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

NHLRC1-related disorder

Pathogenic:1

Dec 20, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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; Romá-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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

PhyloP100

6.6

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.85

Sift

Uncertain

0.024

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.83

MutPred

0.84

Gain of sheet (P = 0.0016);

MVP

0.99

MPC

1.2

ClinPred

0.84

GERP RS

4.3

PromoterAI

0.11

Neutral

(source)

Varity_R

0.61

gMVP

0.83

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over