VCV000283229.16 - ClinVar

NM_005476.7(GNE):c.1807C>T (p.Leu603Phe)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005476.7(GNE):c.1807C>T (p.Leu603Phe)

Variation ID: 283229 Accession: VCV000283229.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9p13.3 9: 36219847 (GRCh38) [ NCBI UCSC ] 9: 36219844 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Jul 15, 2024	Apr 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005476.7:c.1807C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005467.1:p.Leu603Phe	missense
NM_001128227.3:c.1900C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001121699.1:p.Leu634Phe	missense
NM_001190383.3:c.1585C>T	NP_001177312.1:p.Leu529Phe	missense
NM_001190384.3:c.1477C>T	NP_001177313.1:p.Leu493Phe	missense
NM_001190388.2:c.1630C>T	NP_001177317.2:p.Leu544Phe	missense
NM_001374797.1:c.1654C>T	NP_001361726.1:p.Leu552Phe	missense
NM_001374798.1:c.1630C>T	NP_001361727.1:p.Leu544Phe	missense
NC_000009.12:g.36219847G>A
NC_000009.11:g.36219844G>A
NG_008246.1:g.62198C>T
LRG_1197:g.62198C>T
LRG_1197t1:c.1900C>T	LRG_1197p1:p.Leu634Phe
LRG_1197t2:c.1807C>T	LRG_1197p2:p.Leu603Phe

... more HGVS ... less HGVS

Protein change

L603F, L634F, L493F, L529F, L552F, L544F

Other names

Canonical SPDI

NC_000009.12:36219846:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA5056424 dbSNP: rs372732220 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GNE		-	-	GRCh38 GRCh37	1051	1129

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jun 24, 2022	RCV000296082.7
GNE myopathy	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Mar 16, 2024	RCV000664508.6
GNE myopathy Sialuria	Pathogenic (1)	criteria provided, single submitter	May 13, 2023	RCV001247004.5
not specified	Uncertain significance (1)	criteria provided, single submitter	Apr 18, 2024	RCV004586657.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Sep 15, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000335207.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GNE Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Dec 24, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	GNE myopathy Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000788480.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (1) PubMed: 24027297
Uncertain significance (Jun 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003815068.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (May 13, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Sialuria GNE myopathy Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001420401.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 22507750‚ 24027297‚ 32505938 Comment: For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more) For these reasons, this variant has been classified as Pathogenic. 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: 283229). This missense change has been observed in individual(s) with GNE-related myopathy (PMID: 22507750, 24027297, 32505938). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs372732220, gnomAD 0.002%). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 634 of the GNE protein (p.Leu634Phe). (less)
Likely pathogenic (Mar 16, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	GNE myopathy Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004199380.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Apr 18, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005077244.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Publications: PubMed (3) PubMed: 24027297‚ 22507750‚ 32505938 Comment: Variant summary: GNE c.1900C>T (p.Leu634Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more) Variant summary: GNE c.1900C>T (p.Leu634Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251450 control chromosomes (gnomAD). c.1900C>T has been reported in the literature in individuals affected with Inclusion Body Myopathy 2 (Mori-Yoshimura_2012, Cho_2014, Paul_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22507750, 24027297, 32505938). ClinVar contains an entry for this variant (Variation ID: 283229). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
Uncertain significance (Jun 22, 2021)	no assertion criteria provided Method: clinical testing	Nonaka myopathy Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002075629.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

For these reasons, this variant has been classified as Pathogenic. 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: 283229). This missense change has been observed in individual(s) with GNE-related myopathy (PMID: 22507750, 24027297, 32505938). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs372732220, gnomAD 0.002%). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 634 of the GNE protein (p.Leu634Phe).

Comment:

Variant summary: GNE c.1900C>T (p.Leu634Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251450 control chromosomes (gnomAD). c.1900C>T has been reported in the literature in individuals affected with Inclusion Body Myopathy 2 (Mori-Yoshimura_2012, Cho_2014, Paul_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22507750, 24027297, 32505938). ClinVar contains an entry for this variant (Variation ID: 283229). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Distal myopathy and thrombocytopenia due to a novel GNE mutation.	Paul P	Journal of the neurological sciences	2020	PMID: 32505938
Mutation profile of the GNE gene in Japanese patients with distal myopathy with rimmed vacuoles (GNE myopathy).	Cho A	Journal of neurology, neurosurgery, and psychiatry	2014	PMID: 24027297
Heterozygous UDP-GlcNAc 2-epimerase and N-acetylmannosamine kinase domain mutations in the GNE gene result in a less severe GNE myopathy phenotype compared to homozygous N-acetylmannosamine kinase domain mutations.	Mori-Yoshimura M	Journal of the neurological sciences	2012	PMID: 22507750
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GNE	-	-	-	-

Text-mined citations for rs372732220 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_005476.7(GNE):c.1807C>T (p.Leu603Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs372732220 ...