rs1209266607

Positions:

• chr9-36249318-C-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The ENST00000396594.8(GNE):​c.131G>C​(p.Cys44Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,940 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 (★★). Synonymous variant affecting the same amino acid position (i.e. C44C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GNE ENST00000396594.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.10

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 strand (size 7) in uniprot entity GLCNE_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in ENST00000396594.8
• PM2: Very rare variant in population databases, with high coverage
• 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 4.032 (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, 0.972
• PP5: Variant 9-36249318-C-G is Pathogenic according to our data. Variant chr9-36249318-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 496947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36249318-C-G is described in Lovd as [Pathogenic]. Variant chr9-36249318-C-G is described in Lovd as [Likely_pathogenic]. Variant chr9-36249318-C-G is described in Lovd as [Likely_pathogenic]. Variant chr9-36249318-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNE	NM_001128227.3	c.131G>C	p.Cys44Ser	missense_variant	2/12	ENST00000396594.8	NP_001121699.1
GNE	NM_005476.7	c.38G>C	p.Cys13Ser	missense_variant	2/12	ENST00000642385.2	NP_005467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNE	ENST00000396594.8	c.131G>C	p.Cys44Ser	missense_variant	2/12	1	NM_001128227.3	ENSP00000379839
GNE	ENST00000642385.2	c.38G>C	p.Cys13Ser	missense_variant	2/12		NM_005476.7	ENSP00000494141	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74370

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GNE myopathy Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2023	Variant summary: GNE c.131G>C (p.Cys44Ser), also referred to as c.89G>C (p.Cys13Ser) in the literature, results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251418 control chromosomes (gnomAD). c.131G>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Inclusion Body Myopathy 2/Distal Myopathy with Rimmed Vacuoles (e.g. Saito_2004, Noguchi_2004, Sim_2013). 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 in vitro and found the UDP-GlcNAc 2-epimerase activity of the variant was approximately 20% of the wild type protein (e.g. Noguchi_2004). The following publications have been ascertained in the context of this evaluation (PMID: 14707127, 14733963, 23549799). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jun 27, 2019	- -
Pathogenic, no assertion criteria provided	research	Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	Feb 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 06, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Sialuria;C1853926:GNE myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 09, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GNE function (PMID: 14707127). 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. ClinVar contains an entry for this variant (Variation ID: 496947). This missense change has been observed in individuals with autosomal recessive distal myopathy with rimmed vacuoles (DMRV) (PMID: 14707127, 14733962, 22507750, 27363342, 28403181, 30390020, 31286697). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 44 of the GNE protein (p.Cys44Ser). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 15, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;.;D;.;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D;D;.
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.90	L;.;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.4	.;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.020	.;D;D;D;D
Sift4G	Uncertain	0.021	.;D;D;D;D
Polyphen		0.90	P;D;P;.;P
Vest4		0.79, 0.79, 0.80, 0.79
MutPred		0.88		Gain of disorder (P = 0.0193);.;Gain of disorder (P = 0.0193);Gain of disorder (P = 0.0193);Gain of disorder (P = 0.0193);
MVP		1.0
MPC		1.5
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.97

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: rs1209266607; hg19: chr9-36249315;