rs762106720

Variant names:

• chr9-36234073-G-A
• rs762106720
• NM_001128227.3:c.922C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 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. R308H) 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:9
• Conservation: PhyloP100: 9.15
• Publications: 11 publications found

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

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001128227.3
• 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: 4.032 (above the threshold of 3.09). GenCC associations: The gene is linked to sialuria, GNE myopathy, congenital myopathy, platelet-type bleeding disorder 19, macrothrombocytopenia, isolated.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 188847.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
GNE	NM_001128227.3	c.922C>T	p.Arg308Cys	missense_variant	Exon 5 of 12	ENST00000396594.8	NP_001121699.1
GNE	NM_005476.7	c.829C>T	p.Arg277Cys	missense_variant	Exon 5 of 12	ENST00000642385.2	NP_005467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNE	ENST00000396594.8	c.922C>T	p.Arg308Cys	missense_variant	Exon 5 of 12	1	NM_001128227.3	ENSP00000379839.3
GNE	ENST00000642385.2	c.829C>T	p.Arg277Cys	missense_variant	Exon 5 of 12		NM_005476.7	ENSP00000494141.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251480 AF XY: 0.0000221

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111904

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GNE myopathy Pathogenic:5

Jul 17, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 10, 2023

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.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. -

Feb 01, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jun 25, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2016

Eurofins Ntd Llc (ga)

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

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sialuria;C1853926:GNE myopathy Pathogenic:1

Apr 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
LIST_S2	Pathogenic	0.99	.;D;D;D;D;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
PhyloP100		9.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.2	.;D;D;.;N;D;D
REVEL	Pathogenic	0.85
Sift	Benign	0.089	.;T;T;.;D;T;T
Sift4G	Benign	0.12	.;T;T;T;T;T;T
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

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