rs121908622

Variant names:

• chr9-36234105-C-T
• rs121908622
• NM_001128227.3:c.890G>A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_005476.7(GNE):​c.797G>A​(p.Arg266Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R266W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNE NM_005476.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.22

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 19 ACMG points.

• PM1: In a helix (size 9) in uniprot entity GLCNE_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005476.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-36234106-G-A 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, 0.951
• PP5: Variant 9-36234105-C-T is Pathogenic according to our data. Variant chr9-36234105-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36234105-C-T is described in Lovd as [Pathogenic]. Variant chr9-36234105-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNE	NM_001128227.3	c.890G>A	p.Arg297Gln	missense_variant	Exon 5 of 12	ENST00000396594.8	NP_001121699.1
GNE	NM_005476.7	c.797G>A	p.Arg266Gln	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.890G>A	p.Arg297Gln	missense_variant	Exon 5 of 12	1	NM_001128227.3	ENSP00000379839.3
GNE	ENST00000642385.2	c.797G>A	p.Arg266Gln	missense_variant	Exon 5 of 12		NM_005476.7	ENSP00000494141.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sialuria Pathogenic:2 Other:1

Apr 20, 2023

Duke University Health System Sequencing Clinic, Duke University Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sialuria;C1853926:GNE myopathy Pathogenic:1

May 22, 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 glutamine, which is neutral and polar, at codon 297 of the GNE protein (p.Arg297Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant sialuria (PMID: 10356312, 11326336; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as R266Q. ClinVar contains an entry for this variant (Variation ID: 6022). 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: 21436238). This variant disrupts the p.Arg297 amino acid residue in GNE. Other variant(s) that disrupt this residue have been observed in individuals with GNE-related conditions (PMID: 10330343), 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	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;.;D;.;.;.;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;.
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.0	L;.;L;.;.;L;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.8	.;N;N;.;N;N;N
REVEL	Pathogenic	0.81
Sift	Benign	0.091	.;T;T;.;D;T;T
Sift4G	Uncertain	0.060	.;T;T;D;T;D;T
Polyphen		1.0	D;D;D;.;.;.;D
Vest4		0.88, 0.92, 0.79, 0.65, 0.84
MutPred		0.82		Loss of MoRF binding (P = 0.0277);.;Loss of MoRF binding (P = 0.0277);.;.;Loss of MoRF binding (P = 0.0277);Loss of MoRF binding (P = 0.0277);
MVP		0.98
MPC		1.6
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.76
gMVP		0.82

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: rs121908622; hg19: chr9-36234102; COSMIC: COSV64952287;