9-36246120-T-A

Position:

chr9-36246120-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM1PP2PP5_Very_StrongBP4

The NM_005476.7(GNE):c.527A>T(p.Asp176Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000489 in 1,614,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

GNE
NM_005476.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 3.64

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 10 ACMG points.

PM1

In a helix (size 2) in uniprot entity GLCNE_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005476.7

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNE. . Gene score misZ 2.5904 (greater than the threshold 3.09). Trascript score misZ 3.9915 (greater than threshold 3.09). GenCC has associacion of gene with macrothrombocytopenia, isolated, platelet-type bleeding disorder 19, sialuria, GNE myopathy.

PP5

Variant 9-36246120-T-A is Pathogenic according to our data. Variant chr9-36246120-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 41233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36246120-T-A is described in Lovd as [Pathogenic]. Variant chr9-36246120-T-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.23645481). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNE	NM_001128227.3 linkuse as main transcript	c.620A>T	p.Asp207Val	missense_variant	3/12	ENST00000396594.8	NP_001121699.1	Q9Y223-2
GNE	NM_005476.7 linkuse as main transcript	c.527A>T	p.Asp176Val	missense_variant	3/12	ENST00000642385.2	NP_005467.1	Q9Y223-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNE	ENST00000396594.8 linkuse as main transcript	c.620A>T	p.Asp207Val	missense_variant	3/12	1	NM_001128227.3	ENSP00000379839.3		Q9Y223-2
GNE	ENST00000642385.2 linkuse as main transcript	c.527A>T	p.Asp176Val	missense_variant	3/12		NM_005476.7	ENSP00000494141.2		Q9Y223-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152240

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:

0.00115

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251312

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000598

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000499

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00169

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000503

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

GNE myopathy

Pathogenic:6Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The GNE c.527A>T (p.Asp176Val) variant is a well-described pathogenic variant (Mori-Yoshimura et al. 2014; Zhao et al. 2015). In the Japanese nationwide patient registry, which includes 121 patients with GNE-related myopathy, the p.Asp176Val variant is found in a homozygous state in one individual, in a compound heterozygous state with the common p.Val572Leu variant in 24 individuals, in a compound heterozygous state with different variants in 29 individuals, and in a heterozygous state in three individuals (Mori-Yoshimura et al. 2014). The p.Asp176Val variant is additionally reported in three other studies in which it is found in 37 patients of Chinese origin including three in a homozygous state and 34 in a compound heterozygous state, and in one Korean patient in a compound heterozygous state (Lu et al; 2011; Choi et al. 2015; Zhao et al. 2015). The p.Asp176Val variant was detected in a heterozygous state in one of 520 control individuals and is reported at a frequency of 0.00046 in the East Asian population of the Exome Aggregation Consortium. Functional studies using a p.Asp176Val transgenic mouse model found that the mouse mimicked the clinical, histopathological, and biochemical features of GNE-related myopathy, however, the p.Asp176Val variant was also reported in a homozygous state in a 71 year old asymptomatic individual (Cho et al. 2014). Although the p.Asp176Val variant has been identified at a high frequency of individuals with GNE-related myopathy, the variability in clinical presentation is suggestive of a milder phenotype and potentially reduced penetrance. Based on the collective evidence, the p.Asp176Val variant is classified as pathogenic for GNE-related myopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 24, 2019	NM_001128227.2(GNE):c.620A>T(D207V, aka D176V) is classified as pathogenic in the context of GNE myopathy. Sources cited for classification include the following: PMID 17704511, 14707127 and 24027297. Classification of NM_001128227.2(GNE):c.620A>T(D207V, aka D176V) 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, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 04, 2021	Variant summary: GNE c.620A>T (p.Asp207Val) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251312 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (5.2e-05 vs 0.0011), allowing no conclusion about variant significance. c.620A>T has been widely reported in the literature in multiple individuals affected with features of Inclusion Body Myopathy 2 (example,Nishino_2002, Noguchi_2004, Ishihara_2008, Choi_2015, Chanana_2017, Miao_2020). 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 (example, Nishino_2002). The most pronounced variant effect results in <10% of normal UDP-N acetylglucosamine 2-epimerase enzyme activity in leukocytes from homozygous as well as compound heterozygous patients with Distal myopathy with rimmed vacuoles (DMRV). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=6)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2016	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 24, 2024

- -

Sialuria;C1853926:GNE myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 207 of the GNE protein (p.Asp207Val). This variant is present in population databases (rs139425890, gnomAD 0.06%). This missense change has been observed in individuals with distal myopathy (PMID: 12473753, 14707127, 18383535, 26161358, 28403181, 29307446). ClinVar contains an entry for this variant (Variation ID: 41233). 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 GNE protein function. Experimental studies have shown that this missense change affects GNE function (PMID: 14707127, 20030229, 24474513, 28895049). For these reasons, this variant has been classified as Pathogenic. -

GNE-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 23, 2024

The GNE c.620A>T variant is predicted to result in the amino acid substitution p.Asp207Val. This variant, alternatively referred to as p.Asp176Val, has been reported in the homozygous and compound heterozygous states in multiple individuals with hereditary inclusion body myopathy (see for example, Nishino et al. 2002. PubMed ID: 12473753; Ishihara et al. 2008. PubMed ID: 18383535; Mori-Yoshimura et al. 2012. PubMed ID: 22507750). This variant is reported in 0.060% of alleles in individuals of East Asian descent in gnomAD. In vitro and in vivo experimental studies suggest this variant affects UDP-GlcNAc 2-epimerase activity and recapitulates hereditary inclusion body myopathy using a mouse model (Noguchi et al. 2004. PubMed ID: 14707127; Mori-Yoshimura et al. 2012. PubMed ID: 22507750). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

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

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.88

MetaRNN

Benign

0.24

T;T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.6

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

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.3

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

REVEL

Pathogenic

0.80

Sift

Uncertain

0.016

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

Sift4G

Benign

0.084

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

Polyphen

0.52

P;P;P;.;.;.;P

Vest4

0.68, 0.66, 0.68, 0.67, 0.67, 0.66

MVP

0.98

MPC

1.1

ClinPred

0.15

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.88

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

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