NM_005476.7(GNE):c.673G>A (p.Asp225Asn) AND GNE myopathy

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 5, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000006402.7

Allele description [Variation Report for NM_005476.7(GNE):c.673G>A (p.Asp225Asn)]

NM_005476.7(GNE):c.673G>A (p.Asp225Asn)

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.673G>A (p.Asp225Asn)

HGVS:

NC_000009.12:g.36236928C>T
NG_008246.1:g.45117G>A
NM_001128227.3:c.766G>A
NM_001190383.3:c.673G>A
NM_001190384.3:c.440-2796G>A
NM_001190388.2:c.496G>A
NM_001374797.1:c.617-2796G>A
NM_001374798.1:c.496G>A
NM_005476.7:c.673G>AMANE SELECT
NP_001121699.1:p.Asp256Asn
NP_001177312.1:p.Asp225Asn
NP_001177317.2:p.Asp166Asn
NP_001361727.1:p.Asp166Asn
NP_005467.1:p.Asp225Asn
LRG_1197t1:c.766G>A
LRG_1197t2:c.673G>A
LRG_1197:g.45117G>A
LRG_1197p1:p.Asp256Asn
LRG_1197p2:p.Asp225Asn
NC_000009.11:g.36236925C>T
NM_001128227.2:c.766G>A

Protein change:

D166N; ASP225ASN

Links:

OMIM: 603824.0011; dbSNP: rs121908630

NCBI 1000 Genomes Browser:

rs121908630

Molecular consequence:

NM_001190384.3:c.440-2796G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001374797.1:c.617-2796G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001128227.3:c.766G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001190383.3:c.673G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001190388.2:c.496G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374798.1:c.496G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005476.7:c.673G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000026585	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 2001)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000791822	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (May 24, 2017)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11528398, 24796702, 26980148, 19917666 Citation Link,
SCV002511603	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 5, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12497639, 11528398 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000026585

OMIM

no assertion criteria provided

Pathogenic
(Sep 1, 2001)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000791822

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(May 24, 2017)

unknown

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV002511603

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 5, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Mutation update for GNE gene variants associated with GNE myopathy.

Celeste FV, Vilboux T, Ciccone C, de Dios JK, Malicdan MC, Leoyklang P, McKew JC, Gahl WA, Carrillo-Carrasco N, Huizing M.

Hum Mutat. 2014 Aug;35(8):915-26. doi: 10.1002/humu.22583. Review.

PubMed [citation]

PMID:: 24796702
PMCID:: PMC4172345

Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, the key enzyme in sialic acid biosynthesis.

Chen SC, Huang CH, Lai SJ, Yang CS, Hsiao TH, Lin CH, Fu PK, Ko TP, Chen Y.

Sci Rep. 2016 Mar 16;6:23274. doi: 10.1038/srep23274.

PubMed [citation]

PMID:: 26980148
PMCID:: PMC4793188

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000026585.3

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

Description

For discussion of the asp225-to-asn (D225N) mutation in the GNE gene that was found in compound heterozygous state in patients with Nonaka myopathy (NM; 605820) by Eisenberg et al. (2001), see 603824.0010.

#	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 Counsyl, SCV000791822.1

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

#	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, SCV002511603.1

#	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.766G>A (p.Asp256Asn) results in a conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251392 control chromosomes. c.766G>A has been reported in the literature in four individuals affected with Inclusion Body Myopathy 2 from a single family, in the compound heterozygous state (Eisenberg_2001). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two submitters classified the variant as VUS while one classified as pathogenic. Based on the evidence outlined above, the variant was classified as likely 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

Last Updated: Mar 5, 2024

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