rs62541771

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_005476.7(GNE):c.1892C>T(p.Ala631Val) variant causes a missense change. The variant allele was found at a frequency of 0.000214 in 1,613,808 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A631T) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

GNE
NM_005476.7 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 6.41

Variant links:

Genes affected

GNE (HGNC:23657): (glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase) The protein encoded by this gene is a bifunctional enzyme that initiates and regulates the biosynthesis of N-acetylneuraminic acid (NeuAc), a precursor of sialic acids. It is a rate-limiting enzyme in the sialic acid biosynthetic pathway. Sialic acid modification of cell surface molecules is crucial for their function in many biologic processes, including cell adhesion and signal transduction. Differential sialylation of cell surface molecules is also implicated in the tumorigenicity and metastatic behavior of malignant cells. Mutations in this gene are associated with sialuria, autosomal recessive inclusion body myopathy, and Nonaka myopathy. Alternative splicing of this gene results in transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

GNE links:

CLTA (HGNC:2090): (clathrin light chain A) Clathrin is a large, soluble protein composed of heavy and light chains. It functions as the main structural component of the lattice-type cytoplasmic face of coated pits and vesicles which entrap specific macromolecules during receptor-mediated endocytosis. This gene encodes one of two clathrin light chain proteins which are believed to function as regulatory elements. Alternative splicing results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 8 and 12. [provided by RefSeq, May 2010]

CLTA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a helix (size 8) in uniprot entity GLCNE_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005476.7

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-36218225-C-T is described in Lovd as [Pathogenic].

PP2

Missense variant in the GNE gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.5904 (below the threshold of 3.09). Trascript score misZ: 3.9915 (above the threshold of 3.09). GenCC associations: The gene is linked to macrothrombocytopenia, isolated, platelet-type bleeding disorder 19, sialuria, GNE myopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 9-36218224-G-A is Pathogenic according to our data. Variant chr9-36218224-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36218224-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNE	NM_001128227.3 link	c.1985C>T	p.Ala662Val	missense_variant	Exon 11 of 12	ENST00000396594.8	NP_001121699.1	Q9Y223-2
GNE	NM_005476.7 link	c.1892C>T	p.Ala631Val	missense_variant	Exon 11 of 12	ENST00000642385.2	NP_005467.1	Q9Y223-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNE	ENST00000396594.8 link	c.1985C>T	p.Ala662Val	missense_variant	Exon 11 of 12	1	NM_001128227.3	ENSP00000379839.3		Q9Y223-2
GNE	ENST00000642385.2 link	c.1892C>T	p.Ala631Val	missense_variant	Exon 11 of 12		NM_005476.7	ENSP00000494141.2		Q9Y223-1

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251482

Hom.:

AF XY:

0.0000956

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000193

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000227

AC:

332

AN:

1461736

Hom.:

Cov.:

AF XY:

0.000209

AC XY:

152

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000286

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.0000966

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:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000172

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

GNE myopathy

Pathogenic:9Other:1

Mar 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GNE c.1985C>T (p.Ala662Val), also referred to as c.1892C>T (p.Ala631Val), results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 251482 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (8.7e-05 vs 0.0011), allowing no conclusion about variant significance. c.1985C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Inclusion Body Myopathy 2 (e.g. Chaouch_2014). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (eg. Noguchi_2004, Sparks_2005). The most pronounced variant effect results in 10%-<30% of normal UDP-GlcNAc 2-epimerase and ManNAc kinase activities. The following publications have been ascertained in the context of this evaluation (PMID: 14707127, 15987957, 24695763). ClinVar contains an entry for this variant (Variation ID: 6035). Based on the evidence outlined above, the variant was classified as pathogenic. -

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1985C>T (p.Ala662Val) is a missense variant in the GNE gene where missense pathogenic variants have been reported. It is located in the kinase domain of the protein, and functional studies have shown that the kinase activity is dramatically reduced in cells carrying this variant (Nogushi et al. 2004). It is absent or not frequent in the control population databases (0% in 1000 genomes and Exome Sequencing Project, and 0.013% in ExAc), and in silico computational algorithms predicted this variant to be deleterious to protein function and exhibits a high CADD score (27.1). Finally, this variant has been described as pathogenic by ClinVar and the Emory Genetics Laboratory. Therefore, this collective evidence supports the classification of the c.1985C>T (p.Ala662Val) as a recessive pathogenic variant for inclusion body myopathy. -

Dec 10, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_001128227.2(GNE):c.1985C>T(A662V) is classified as pathogenic in the context of GNE myopathy. Sources cited for classification include the following: PMID 22343627, 15987957, 14707127, 12473769, 12177386, 12497639, 24695763 and 16503651. Classification of NM_001128227.2(GNE):c.1985C>T(A662V) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Dec 03, 2019

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2, PM5, PP2, PP3, PP5 -

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The c.1985C>T (p.A662V) variant has been observed in the homozygous or compound heterozygous state in individuals with GNE myopathy (PMID: 12177386; 12473769; 12497639; 15136692; 19596068; 21131200; 22196754; 22883483; 24695763). -

not provided

Pathogenic:6

Apr 18, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2, PM3_strong, PS3, PS4 -

Apr 03, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 21, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34676965, 19917666, 15987957, 22507750, 12177386, 16503651, 31127727, 35138478, 26968811, 24796702, 38674419, 37510394, 24695763, 14707127) -

Jun 24, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sialuria;C1853926:GNE myopathy

Pathogenic:3

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 662 of the GNE protein (p.Ala662Val). This variant is present in population databases (rs62541771, gnomAD 0.02%). This missense change has been observed in individuals with GNE myopathy (PMID: 24796702). It is commonly reported in individuals of British and Chinese ancestry (PMID: 22196754, 24695763). This variant is also known as p.Ala631Val. ClinVar contains an entry for this variant (Variation ID: 6035). 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) has been performed 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 GNE protein function. Experimental studies have shown that this missense change affects GNE function (PMID: 14707127, 15987957, 16503651). For these reasons, this variant has been classified as Pathogenic. -

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sialuria;C1853926:GNE myopathy;C5935593:Thrombocytopenia 12 with or without myopathy

Pathogenic:1

Jun 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colon cancer

Pathogenic:1

Mar 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thrombocytopenia 12 with or without myopathy

Pathogenic:1

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;.;D;.;.;.;D

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.97

.;D;D;D;D;D;.

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.3

M;.;M;.;.;.;M

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.97

.;N;N;.;N;N;N

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

.;D;D;.;D;D;D

Sift4G

Uncertain

0.056

.;T;T;T;T;D;T

Polyphen

1.0

D;D;D;.;.;.;D

Vest4

0.92, 0.94, 0.90, 0.86, 0.83, 0.94

MutPred

0.96

Gain of MoRF binding (P = 0.0897);.;Gain of MoRF binding (P = 0.0897);.;.;.;Gain of MoRF binding (P = 0.0897);

MVP

0.99

MPC

1.3

ClinPred

0.34

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.90

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