rs199877522

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5PP2PP5_Very_Strong

The NM_005476.7(GNE):c.1132G>T(p.Asp378Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,612,536 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D378H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

GNE
NM_005476.7 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11O:2

Conservation

PhyloP100: 2.90

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 11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-36227397-C-G 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.

PP5

Variant 9-36227397-C-A is Pathogenic according to our data. Variant chr9-36227397-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 283278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36227397-C-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.1225G>T	p.Asp409Tyr	missense_variant	Exon 7 of 12	ENST00000396594.8	NP_001121699.1	Q9Y223-2
GNE	NM_005476.7 link	c.1132G>T	p.Asp378Tyr	missense_variant	Exon 7 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.1225G>T	p.Asp409Tyr	missense_variant	Exon 7 of 12	1	NM_001128227.3	ENSP00000379839.3		Q9Y223-2
GNE	ENST00000642385.2 link	c.1132G>T	p.Asp378Tyr	missense_variant	Exon 7 of 12		NM_005476.7	ENSP00000494141.2		Q9Y223-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.000368

Gnomad OTH

AF:

0.000960

GnomAD3 exomes

AF:

0.000159

AC:

AN:

251400

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.000343

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000393

AC:

574

AN:

1460430

Hom.:

Cov.:

AF XY:

0.000356

AC XY:

259

AN XY:

726622

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000475

Gnomad4 OTH exome

AF:

0.000630

GnomAD4 genome

AF:

0.000204

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.000960

Alfa

AF:

0.000238

Hom.:

Bravo

AF:

0.000223

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

GNE myopathy

Pathogenic:5Other:1

Aug 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp409Tyr variant in GNE has been reported in at least 12 compound heteroz ygous patients from 9 families (Chaouch 2014). In addition, this variant has bee n identified in 0.01% (14/121,022) of chromosomes by the Exome Aggregation Conso rtium (ExAC, http://exac.broadinstitute.org; dbSNP rs199877522). Although this v ariant has been seen in the general population, its frequency is low enough to b e consistent with a carrier frequency. In vitro functional studies support an im pact to protein function (Noguchi 2004, Penner 2006). In summary, this variant m eets criteria to be classified as pathogenic for GNE-related myopathy based on g enetic and functional data. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 09, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variants in the GNE gene are known to cause GNE-related myopathies. The GNE c.1132G>T (p.Asp378Tyr) missense variant has been reported in at least three studies in which it is found in a compound heterozygous state in a total of five individuals with GNE-related myopathy (two of whom were related) (Eisenberg et al. 2003; Nishino et al. 2002; Leoyklang et al. 2014). The p.Asp378Tyr variant was absent from 50 control subjects and is reported at a frequency of 0.000324 in the European (non-Finnish) population of the Genome Aggregation Database. In vitro studies showed that p.Asp378Tyr variant was associated with 60% reduction of epimerase and a 50% reduction of kinase activity compared to wild type (Penner et al., 2006). Based on the evidence, the p.Asp378Tyr variant is classified as pathogenic for GNE-related myopathies. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Feb 05, 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.1225G>T (p.Asp409Tyr) 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 0.00016 in 251400 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (0.00016 vs 0.0011), allowing no conclusion about variant significance. c.1225G>T has been reported in the literature in multiple individuals affected with Inclusion Body Myopathy 2 (Noguchi_2004, Pogoryelova_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant results in reduced enzyme activity (Noguchi_2004). The following publications have been ascertained in the context of this evaluation (PMID: 14707127, 30842975). ClinVar contains an entry for this variant (Variation ID: 283278). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 26, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_001128227.2(GNE):c.1225G>T(D409Y) is classified as pathogenic in the context of GNE myopathy. Sources cited for classification include the following: PMID 12473753, 24695763, 14707127 and 16503651. Classification of NM_001128227.2(GNE):c.1225G>T(D409Y) 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. -

not provided

Pathogenic:3

Mar 01, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (60% reduction in epimerase activity and 50% reduction in kinase activity as compared to wild type) (Penner et al., 2006); Missense variants in this gene are often considered pathogenic (HGMD); 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: 29305133, 12497639, 24695763, 16503651, 14707127, 12473753, 29382405, 19917666, 30467490, 30609409, 31127727, 24796702, 19596068, 27829678, 25123033, 24027297, 20301439, 29997562, 28641925, 30564623, 12325084, 26968811) -

Sep 11, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sialuria;C1853926:GNE myopathy

Pathogenic:1Other:1

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 07-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 409 of the GNE protein (p.Asp409Tyr). This variant is present in population databases (rs199877522, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive GNE-related myopathy (PMID: 12473753, 12497639, 24695763). It is commonly reported in individuals of European ancestry (PMID: 12473753, 12497639, 24695763). This variant is also known as p.D378Y. ClinVar contains an entry for this variant (Variation ID: 283278). 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, 16503651). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Nov 17, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1225G>T (p.D409Y) alteration is located in coding exon 7 of the GNE gene. This alteration results from a G to T substitution at nucleotide position 1225, causing the aspartic acid (D) at amino acid position 409 to be replaced by a tyrosine (Y)._x000D_ _x000D_ Based on the available evidence, the GNE c.1225G>T (p.D409Y) alteration is classified as pathogenic for autosomal recessive Nonaka myopathy; however, its clinical significance for autosomal dominant sialuria is uncertain. Based on data from gnomAD, the T allele has an overall frequency of 0.016% (45/282778) total alleles studied. The highest observed frequency was 0.033% (42/129128) of European (non-Finnish) alleles. This variant has been described as a British founder mutation after being reported in compound heterozygous form in numerous individuals affected with clinical and pathological findings consistent with GNE-related myopathy (Chaouch, 2014; Carrillo, 2018; Soule, 2018). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

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

Pathogenic:1

Jun 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

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

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.67

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.81

L;.;L;.;.;L;L

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.9

.;D;D;N;D;D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0060

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

Polyphen

1.0

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

Vest4

0.87, 0.88, 0.83, 0.79, 0.75, 0.87

MVP

0.99

MPC

1.6

ClinPred

0.43

GERP RS

6.0

Varity_R

0.90

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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