rs762106720

Positions:

• chr9-36234073-G-A
• chr9-36234073-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PP2 PP3_Strong PP5_Very_Strong

The NM_001128227.3(GNE):​c.922C>T​(p.Arg308Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,780 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R308G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: GNE NM_001128227.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.15

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a helix (size 3) in uniprot entity GLCNE_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001128227.3
• PP2: Missense variant where missense usually causes diseases, GNE
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 9-36234073-G-A is Pathogenic according to our data. Variant chr9-36234073-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36234073-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNE	NM_001128227.3	c.922C>T	p.Arg308Cys	missense_variant	5/12	ENST00000396594.8
GNE	NM_005476.7	c.829C>T	p.Arg277Cys	missense_variant	5/12	ENST00000642385.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNE	ENST00000396594.8	c.922C>T	p.Arg308Cys	missense_variant	5/12	1	NM_001128227.3
GNE	ENST00000642385.2	c.829C>T	p.Arg277Cys	missense_variant	5/12		NM_005476.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251480 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461780 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GNE myopathy Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 17, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 01, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 03, 2021	NM_001128227.2(GNE):c.922C>T(R308C) is a missense variant classified as likely pathogenic in the context of GNE myopathy. R308C has been observed in cases with relevant disease (PMID: 24027297, 24695763, 22231866, 27858732, 29997562, 29480215). Functional assessments of this variant are not available in the literature. R308C has been observed in population frequency databases (gnomAD: EAS 0.01%). NM_001128227.2(GNE):c.922C>T(R308C) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 10, 2023	Variant summary: GNE c.922C>T (p.Arg308Cys) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251480 control chromosomes. c.922C>T has been reported in the literature as biallelic genotypes in multiple individuals affected with GNE/Inclusion Body Myopathy 2 (example, Mori-Yoshimura_2012, Cerino_2015). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 27858732, 24695763, 22507750, 22231866). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.829C>Tp.Arg277Cys in GNE gene has been reported previously in homozygous and compoundheterozygous state in multiple individuals with GNE Myopathy Bugiardini E, et al., 2018, Chaouch A, et al., 2014. The variant has0.002% allele frequency in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant disrupts thep.Arg308 amino acid residue in GNE. Other variants that disrupt this residue have been observed in individuals with GNE-relatedconditions Cho A, et al., 2014. It has also been observed to segregate with disease in related individuals. This variant has beenreported to the ClinVar database as Pathogenic/Likely Pathogenic.The amino acid Arginine at position 277 is changed to aCysteine changing protein sequence and it might alter its composition and physico-chemical properties.The amino acid changep.Arg277Cys in GNE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant hasbeen classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 25, 2022	- -

Sialuria;C1853926:GNE myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 27, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 308 of the GNE protein (p.Arg308Cys). This variant is present in population databases (rs762106720, gnomAD 0.01%). This missense change has been observed in individuals with distal myopathy (PMID: 18555875, 22507750, 24027297, 24695763, 29480215). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg277Cys. ClinVar contains an entry for this variant (Variation ID: 188847). 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. This variant disrupts the p.Arg308 amino acid residue in GNE. Other variant(s) that disrupt this residue have been observed in individuals with GNE-related conditions (PMID: 24027297), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;.;D;.;.;.;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.1	L;.;L;.;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
Polyphen		1.0	D;D;D;.;.;.;D
Vest4		0.89, 0.92, 0.87, 0.84, 0.86, 0.92
MutPred		0.90		Loss of MoRF binding (P = 0.0224);.;Loss of MoRF binding (P = 0.0224);.;.;Loss of MoRF binding (P = 0.0224);Loss of MoRF binding (P = 0.0224);
MVP		0.99
MPC		1.6
ClinPred		0.72	D
GERP RS		5.8
Varity_R		0.59
gMVP		0.92

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

Other links and lift over

dbSNP: rs762106720; hg19: chr9-36234070; COSMIC: COSV64951631;