rs28937594

Variant names:

• chr9-36217399-A-G
• rs28937594
• NM_001128227.3:c.2228T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1 PP2 PP3_Moderate PP5_Very_Strong BS1_Supporting

The NM_001128227.3(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 NM_001128227.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:24 O:1
• Conservation: PhyloP100: 8.89
• Publications: 100 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 12 ACMG points.

• PM1: In a hotspot region, there are 3 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, 0.924
• PP5: Variant 9-36217399-A-G is Pathogenic according to our data. Variant chr9-36217399-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 6025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000233 (34/1461192) while in subpopulation MID AF = 0.00277 (16/5768). AF 95% confidence interval is 0.00174. There are 1 homozygotes in GnomAdExome4. There are 20 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

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

Ensembl

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

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

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251286 AF XY: 0.0000442

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111366

Other (OTH) AF: 0.0000331 AC: 2 AN: 60384

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

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000397 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:24 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GNE myopathy Pathogenic:13 Other:1

-

FirmaLab, FirmaLab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 11, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Sep 27, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 15147877, 15670773). In silico tool predictions suggest a damaging effect of the variant on gene or gene product [REVEL: 0.76 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006025 /PMID: 11528398 /3billion dataset). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 11528398). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 20, 2024

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.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. -

Feb 05, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2014

Sema4, Sema4

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

8 patients from 7 non-Jewish Persian families were homozygous for this variant -

Oct 27, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3 PM2 PP2 PP3 PP5(strong) -

Mar 23, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 11, 2019

Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 05, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Hadassah Hebrew University Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Pathogenic:4

Apr 10, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 13, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Dec 09, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_moderate, PM2, PM3, PP5 -

Sialuria Pathogenic:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 19, 2022

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PM2, PM3, PP3 -

Sialuria;C1853926:GNE myopathy Pathogenic:2

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence 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 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. -

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sialuria;C1853926:GNE myopathy;C5935593:Thrombocytopenia 12 with or without myopathy Pathogenic:2

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GNE-related disorder Pathogenic:1

Aug 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		8.9
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
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: rs28937594; hg19: chr9-36217396;