rs28937594

Positions:

• chr9-36217399-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000396594.8(GNE):​c.2228T>C​(p.Met743Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,382 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (1 hom.)
• Consequence: GNE ENST00000396594.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 8.89

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 13 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, 4 uncertain in ENST00000396594.8
• 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, 0.924
• PP5: Variant 9-36217399-A-G is Pathogenic according to our data. Variant chr9-36217399-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 6025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36217399-A-G is described in Lovd as [Pathogenic]. Variant chr9-36217399-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNE	NM_001128227.3	c.2228T>C	p.Met743Thr	missense_variant	12/12	ENST00000396594.8	NP_001121699.1
GNE	NM_005476.7	c.2135T>C	p.Met712Thr	missense_variant	12/12	ENST00000642385.2	NP_005467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNE	ENST00000396594.8	c.2228T>C	p.Met743Thr	missense_variant	12/12	1	NM_001128227.3	ENSP00000379839
GNE	ENST00000642385.2	c.2135T>C	p.Met712Thr	missense_variant	12/12		NM_005476.7	ENSP00000494141	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251286 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135840

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461192 Hom.: 1 Cov.: 31 AF XY: 0.0000275 AC XY: 20 AN XY: 726944

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74356

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000176 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

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:12 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Sema4, Sema4	Nov 01, 2014	8 patients from 7 non-Jewish Persian families were homozygous for this variant -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 11, 2004	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_005476.5(GNE):c.2135T>C(M712T) is classified as pathogenic in the context of GNE myopathy. Sources cited for classification include the following: PMID 21873062, 11528398, 12497639, 20300792 and 15987957. Classification of NM_005476.5(GNE):c.2135T>C(M712T) 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.‚Äã -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 23, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	FirmaLab, FirmaLab	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Hadassah Hebrew University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 05, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006025, PMID:11528398). The variant was co-segregated with Nonaka myopathy in multiple affected family members with additional meioses meeting moderate evidence levels (PMID: 11528398). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 15670773, 15147877). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.756>=0.6, 3CNET: 0.836>=0.75). A missense variant is a common mechanism. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000398). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 05, 2022	The p.Met743Thr variant in GNE (also reported in literature as Met712Thr) has been reported in >50 individuals with inclusion body myopathy in the homozygous and compound heterozygous state and segregated with disease in >50 affected individuals from multiple families (Eisenberg 2001 PMID: 11528398, Broccolini 2002 PMID: 12473780, Grandis 2010 PMID: 20300792, Khademian 2013 PMID: 23278550). It has been found in the homozygous state in some apparently asymptomatic family members which could give some evidence to reduced penetrance (Argov 2003 PMID: 1274324). It has also been identified in 0.001% (1/68034) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 6025). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro and in vivo functional studies support some impact on protein function, including increased glycosphingolipids in cells (Salama 2005 PMID: 15670773, Sparks 2005 PMID: 15987957, Patzel 2013 PMID: 24136589). Mouse models homozygous for the Met743Thr variant showed >90% lethality, severe hematuria, proteinuria and glomerulopathy, though in a later study variable phenotypes of mice were found (Kakani 2012 PMID: 22322304, Sela 2013 PMID: 23238814, Patzel 2013 PMID: 24136589). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive GNE myopathy. ACMG/AMP Criteria applied: PP1_Strong, PM3, PS3_Moderate, PM2_Supporting, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 20, 2024	Variant summary: GNE c.2228T>C (p.Met743Thr) also known as p.Met712Thr, results in a non-conservative amino acid change in 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 4e-05 in 251286 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (4e-05 vs 0.0011), allowing no conclusion about variant significance. c.2228T>C has been reported as the common Persian Jewish mutation in the literature in multiple individuals affected with Inclusion Body Myopathy 2 from Middle East (example, Argov_2003). 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. The most pronounced variant effect results in impared GNE function and accumulated Glycosphingolipid levels in both primary fibroblasts from patients and knock-in mice with homozygous p.Met743Thr (Patzel_2014). The following publications have been ascertained in the context of this evaluation (PMID: 12743242, 24136589). ClinVar contains an entry for this variant (Variation ID: 6025). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 09, 2019	PS3, PS4_moderate, PM2, PM3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2022	Published functional studies demonstrate reduced activity compared to wild-type, presumably due to the introduction of an additional phosphorylation/O-GlcNAcylation site as the M743T variant shows increased O-GlcNAcylation as compared to wild-type (Bennmann et al., 2016); The majority of missense variants in this gene are considered pathogenic (HGMD); A founder variant common in the Persian Jewish population (Eisenberg et al., 2001); This variant is associated with the following publications: (PMID: 24136589, 22975760, 20300792, 27023225, 23278550, 17673919, 22322304, 15670773, 15147877, 19917666, 22507750, 21873062, 23238814, 27037841, 15987957, 11528398, 25966635, 12473780, 27671536, 24264357, 28267778, 15136692, 34426522, 31589614, 19787087) -

Sialuria;C1853926:GNE myopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 743 of the GNE protein (p.Met743Thr). This variant is present in population databases (rs28937594, gnomAD 0.004%). This missense change has been observed in individuals with inclusion body myopathy (PMID: 11528398, 20300792, 23278550). It is commonly reported in individuals of Persian ancestry (PMID: 11528398, 20300792, 23278550). This variant is also known as c.2186T>C (p.Met712Thr). ClinVar contains an entry for this variant (Variation ID: 6025). 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: 15147877, 15670773). For these reasons, this variant has been classified as Pathogenic. -

Sialuria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

GNE-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2024

The GNE c.2228T>C variant is predicted to result in the amino acid substitution p.Met743Thr. This variant is also known as (g.36217396A>G, c.2135T>C, p.Met712Thr with alternative transcript NM_005476.5). This variant has been reported as a pathogenic founder variant in certain populations (Persian-Jewish) and is well documented to be causative for GNE myopathy (Eisenberg et al. 2001. PubMed ID: 11528398; Mori-Yoshimura et al. 2012. PubMed ID: 22507750; Haghighi et al. 2016. PubMed ID: 25966635). Enzymatic studies and mouse models with the c.2228T>C variant support the pathogenicity of this variant (Sparks et al. 2005. PubMed ID: 15987957; Patzel et al. 2014. PubMed ID: 24136589). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and is interpreted as pathogenic in ClinVar by many outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/6025/). This variant is interpreted as pathogenic for recessive GNE myopathy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.79	D;.;D;.;.;.;D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;D;D;D;D;.
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.4	M;.;M;.;.;.;M
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.92	.;N;N;.;N;N;N
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	.;D;D;.;D;D;D
Sift4G	Uncertain	0.018	.;D;D;D;D;D;D
Polyphen		0.011	B;B;B;.;.;.;B
Vest4		0.60, 0.84, 0.67, 0.63, 0.73, 0.81
MutPred		0.87		Gain of catalytic residue at M712 (P = 0.0067);.;Gain of catalytic residue at M712 (P = 0.0067);.;.;.;Gain of catalytic residue at M712 (P = 0.0067);
MVP		0.99
MPC		0.69
ClinPred		0.20	T
GERP RS		5.7
Varity_R		0.69
gMVP		0.94

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: rs28937594; hg19: chr9-36217396;