NM_005476.7(GNE):c.2135T>C (p.Met712Thr) AND GNE myopathy

Germline classification:: Pathogenic (13 submissions)
Last evaluated:: Mar 23, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000006396.23

Allele description [Variation Report for NM_005476.7(GNE):c.2135T>C (p.Met712Thr)]

NM_005476.7(GNE):c.2135T>C (p.Met712Thr)

Gene:

GNE:glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9p13.3

Genomic location:

Preferred name:

NM_005476.7(GNE):c.2135T>C (p.Met712Thr)

HGVS:

NC_000009.12:g.36217399A>G
NG_008246.1:g.64646T>C
NM_001128227.3:c.2228T>C
NM_001190383.3:c.1913T>C
NM_001190384.3:c.1805T>C
NM_001190388.2:c.1958T>C
NM_001374797.1:c.1982T>C
NM_001374798.1:c.1958T>C
NM_005476.7:c.2135T>CMANE SELECT
NP_001121699.1:p.Met743Thr
NP_001177312.1:p.Met638Thr
NP_001177313.1:p.Met602Thr
NP_001177317.2:p.Met653Thr
NP_001361726.1:p.Met661Thr
NP_001361727.1:p.Met653Thr
NP_005467.1:p.Met712Thr
LRG_1197t1:c.2228T>C
LRG_1197t2:c.2135T>C
LRG_1197:g.64646T>C
LRG_1197p1:p.Met743Thr
LRG_1197p2:p.Met712Thr
NC_000009.11:g.36217396A>G
NM_001128227.2:c.2228T>C
NM_005476.5:c.2135T>C
NM_005476.7:c.2135T>C
p.Met712Thr

Protein change:

M602T; MET712THR

Links:

OMIM: 603824.0005; dbSNP: rs28937594

NCBI 1000 Genomes Browser:

rs28937594

Molecular consequence:

NM_001128227.3:c.2228T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001190383.3:c.1913T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001190384.3:c.1805T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001190388.2:c.1958T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374797.1:c.1982T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374798.1:c.1958T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_005476.7:c.2135T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: GNE myopathy (NM)
Synonyms:: Nonaka myopathy; Nonaka distal myopathy; INCLUSION BODY MYOPATHY, HEREDITARY, AUTOSOMAL RECESSIVE; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011603; MedGen: C1853926; Orphanet: 602; OMIM: 605820

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000026578	OMIM	no assertion criteria provided	Pathogenic (May 11, 2004)	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 11528398, 12473780, 12743242, 15136692
SCV000058062	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 24027297, 12473753, 27829678, 20301439
SCV000106038	FirmaLab, FirmaLab	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV000196518	Sema4, Sema4	no assertion criteria provided	Pathogenic (Nov 1, 2014)	germline	clinical testing
SCV000882763	Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	no assertion criteria provided	Pathogenic (Feb 11, 2019)	inherited	research
SCV001190834	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Pathogenic (Feb 5, 2020)	germline	clinical testing
SCV001194231	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 20, 2019)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21873062, 11528398, 12497639, 20300792, 15987957 Citation Link,
SCV001458426	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002318651	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 22, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15670773, 15147877, 11528398, 25741868
SCV004099503	Hadassah Hebrew University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004199375	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 23, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004813788	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 20, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24136589, 12743242 Citation Link,
SCV004848011	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 5, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	9	7	not provided	1	yes	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	inherited	yes	1	not provided	not provided	not provided	not provided	research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

An Italian family with autosomal recessive inclusion-body myopathy and mutations in the GNE gene.

Broccolini A, Pescatori M, D'Amico A, Sabino A, Silvestri G, Ricci E, Servidei S, Tonali PA, Mirabella M.

Neurology. 2002 Dec 10;59(11):1808-9. No abstract available.

PubMed [citation]

PMID:: 12473780

Distal myopathy with rimmed vacuoles (DMRV): new GNE mutations and splice variant.

Tomimitsu H, Shimizu J, Ishikawa K, Ohkoshi N, Kanazawa I, Mizusawa H.

Neurology. 2004 May 11;62(9):1607-10.

PubMed [citation]

PMID:: 15136692

See all PubMed Citations (16)

Details of each submission

From OMIM, SCV000026578.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

Description

In 47 Middle Eastern Jewish families, Eisenberg et al. (2001) found that affected individuals with Nonaka myopathy (NM; 605820), which the authors called hereditary inclusion body myopathy (HIBM), had a 2186T-C transition in exon 12 of the GNE gene, resulting in a met712-to-thr (M712T) amino acid change in the kinase domain of the protein.

In 2 second cousins from an Italian family diagnosed with HIBM, Broccolini et al. (2002) identified compound heterozygosity for mutations in the GNE gene: M712T and a novel mutation (M171V; 603824.0016). The authors noted that it was the first report of the M712T mutation in patients of non-Middle Eastern descent.

Argov et al. (2003) identified homozygosity for the M712T mutation in 129 Middle Eastern patients diagnosed with HIBM from 55 families. Eleven patients had atypical features: 5 had involvement of the quadriceps muscle, 2 patients did not have distal weakness, 3 patients had facial weakness, and 1 patient had perivascular inflammation. There were 5 unaffected individuals with the homozygous mutation from 5 different HIBM families, including 2 who were 50 and 68 years old. The families included Middle Eastern Jews, Karaites, and Arab Muslims of Palestinian and Bedouin origin. Argov et al. (2003) offered a detailed historical perspective of the different cultures, and concluded that this founder mutation is approximately 1,300 years old and is not limited to those of Jewish descent.

In a Japanese patient with Nonaka myopathy, Tomimitsu et al. (2004) identified compound heterozygosity for the M712T mutation and the A631V mutation (603824.0015). The findings indicated that Nonaka myopathy and what was previously called hereditary inclusion body myopathy are identical disorders.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000058062.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From FirmaLab, FirmaLab, SCV000106038.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing (GTR000327733)	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided	(GTR000327733)	not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV000196518.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	8	not provided	yes	clinical testing	not provided

Description

age of onset 19-30

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		8	not provided	7	not provided

From Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, SCV000882763.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001190834.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001194231.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.â€šÃ„Ã¶âˆšÃ‘âˆšÂ£

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001458426.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002318651.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Hadassah Hebrew University Medical Center, SCV004099503.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004199375.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004813788.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848011.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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