rs62541771

Positions:

• chr9-36218224-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_005476.7(GNE):​c.1892C>T​(p.Ala631Val) variant causes a missense change. The variant allele was found at a frequency of 0.000214 in 1,613,808 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A631T) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: GNE NM_005476.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 6.41

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 17 ACMG points.

• PM1: In a helix (size 8) in uniprot entity GLCNE_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005476.7
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-36218225-C-T is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 9-36218224-G-A is Pathogenic according to our data. Variant chr9-36218224-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36218224-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNE	NM_001128227.3	c.1985C>T	p.Ala662Val	missense_variant	11/12	ENST00000396594.8	NP_001121699.1
GNE	NM_005476.7	c.1892C>T	p.Ala631Val	missense_variant	11/12	ENST00000642385.2	NP_005467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNE	ENST00000396594.8	c.1985C>T	p.Ala662Val	missense_variant	11/12	1	NM_001128227.3	ENSP00000379839.3
GNE	ENST00000642385.2	c.1892C>T	p.Ala631Val	missense_variant	11/12		NM_005476.7	ENSP00000494141.2

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000875 AC: 22 AN: 251482 Hom.: 0 AF XY: 0.0000956 AC XY: 13 AN XY: 135914

Gnomad AFR exome AF: 0.00

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: 0.000193

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000227 AC: 332 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.000209 AC XY: 152 AN XY: 727184

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000286

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74286

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000172 Hom.: 0

Bravo AF: 0.000144

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GNE myopathy Pathogenic:9 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_001128227.2(GNE):c.1985C>T(A662V) is classified as pathogenic in the context of GNE myopathy. Sources cited for classification include the following: PMID 22343627, 15987957, 14707127, 12473769, 12177386, 12497639, 24695763 and 16503651. Classification of NM_001128227.2(GNE):c.1985C>T(A662V) 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 10, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	-	The c.1985C>T (p.Ala662Val) is a missense variant in the GNE gene where missense pathogenic variants have been reported. It is located in the kinase domain of the protein, and functional studies have shown that the kinase activity is dramatically reduced in cells carrying this variant (Nogushi et al. 2004). It is absent or not frequent in the control population databases (0% in 1000 genomes and Exome Sequencing Project, and 0.013% in ExAc), and in silico computational algorithms predicted this variant to be deleterious to protein function and exhibits a high CADD score (27.1). Finally, this variant has been described as pathogenic by ClinVar and the Emory Genetics Laboratory. Therefore, this collective evidence supports the classification of the c.1985C>T (p.Ala662Val) as a recessive pathogenic variant for inclusion body myopathy. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Jul 14, 2022	PM1, PM2, PM5, PP2, PP3, PP5 -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Dec 03, 2019	- -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The c.1985C>T (p.A662V) variant has been observed in the homozygous or compound heterozygous state in individuals with GNE myopathy (PMID: 12177386; 12473769; 12497639; 15136692; 19596068; 21131200; 22196754; 22883483; 24695763). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 12, 2024	Variant summary: GNE c.1985C>T (p.Ala662Val), also referred to as c.1892C>T (p.Ala631Val), 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 8.7e-05 in 251482 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (8.7e-05 vs 0.0011), allowing no conclusion about variant significance. c.1985C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Inclusion Body Myopathy 2 (e.g. Chaouch_2014). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (eg. Noguchi_2004, Sparks_2005). The most pronounced variant effect results in 10%-<30% of normal UDP-GlcNAc 2-epimerase and ManNAc kinase activities. The following publications have been ascertained in the context of this evaluation (PMID: 14707127, 15987957, 24695763). ClinVar contains an entry for this variant (Variation ID: 6035). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2024	Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34676965, 19917666, 15987957, 22507750, 12177386, 16503651, 31127727, 35138478, 26968811, 24796702, 38674419, 37510394, 24695763, 14707127) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 18, 2023	PP3, PM2, PM3_strong, PS3, PS4 -

Sialuria;C1853926:GNE myopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 662 of the GNE protein (p.Ala662Val). This variant is present in population databases (rs62541771, gnomAD 0.02%). This missense change has been observed in individuals with GNE myopathy (PMID: 24796702). It is commonly reported in individuals of British and Chinese ancestry (PMID: 22196754, 24695763). This variant is also known as p.Ala631Val. ClinVar contains an entry for this variant (Variation ID: 6035). 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, 15987957, 16503651). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

Sialuria;C1853926:GNE myopathy;C5935593:Thrombocytopenia 12 with or without myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 04, 2024

- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 12, 2024

- -

Thrombocytopenia 12 with or without myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;.;D;.;.;.;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.97	.;D;D;D;D;D;.
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.3	M;.;M;.;.;.;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.97	.;N;N;.;N;N;N
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	.;D;D;.;D;D;D
Sift4G	Uncertain	0.056	.;T;T;T;T;D;T
Polyphen		1.0	D;D;D;.;.;.;D
Vest4		0.92, 0.94, 0.90, 0.86, 0.83, 0.94
MutPred		0.96		Gain of MoRF binding (P = 0.0897);.;Gain of MoRF binding (P = 0.0897);.;.;.;Gain of MoRF binding (P = 0.0897);
MVP		0.99
MPC		1.3
ClinPred		0.34	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.90

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: rs62541771; hg19: chr9-36218221;