Submissions for variant NM_005476.7(GNE):c.2086G>A (p.Val696Met)

dbSNP: rs121908627

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255973	SCV000321744	pathogenic	not provided	2021-11-30	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 25002140, 20059379, 24796702, 24695763, 24707269, 11528398, 27535533, 27829678, 20175955, 19917666, 28717665, 27457812, 24005727, 29997562, 12497639, 16810679, 25182749, 25617006, 14972325, 21708040, 29480215, 30564623, 31589614, 33250842, 33197058)
GenePathDx, GenePath diagnostics	RCV000202424	SCV000574533	pathogenic	GNE myopathy	2017-03-01	criteria provided, single submitter	clinical testing	34 years old female, no family history, started having frequent falls at the age of 29 years of age followed by progressively increasing weakness of lower limbs. The weakness appears to be more in distal areas than proximal limb and lower limb is affected more than upper limbs. Next generation DNA sequencing of peripheral blood sample has revealed the presence of two pathogenic variants c.2086 G>A and c.1571C>T in the GNE gene consistent with the diagnosis of Nonaka myopathy or inclusion body myopathy 2/ distal myopathy with rimmed vacuoles.
Invitae	RCV000763616	SCV000638332	pathogenic	GNE myopathy; Sialuria	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 727 of the GNE protein (p.Val727Met). This variant is present in population databases (rs121908627, gnomAD 1.4%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with autosomal recessive GNE myopathy/distal myopathy with rimmed vacuoles (PMID: 11528398, 12497639, 20175955, 21708040, 23437777, 24005727, 25182749, 27829678, 28320138, 28717665). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Val696Met. ClinVar contains an entry for this variant (Variation ID: 6028). 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. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000255973	SCV000700541	pathogenic	not provided	2018-04-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763616	SCV000894470	likely pathogenic	GNE myopathy; Sialuria	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000763616	SCV001163610	pathogenic	GNE myopathy; Sialuria		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000255973	SCV001248053	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001167212	SCV001329679	likely benign	Sialuria	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Baylor Genetics	RCV000202424	SCV001527753	pathogenic	GNE myopathy	2018-06-27	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000255973	SCV001714898	pathogenic	not provided	2020-10-15	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000202424	SCV001984099	likely pathogenic	GNE myopathy	2020-04-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255973	SCV002024875	pathogenic	not provided	2023-11-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202424	SCV002041619	likely pathogenic	GNE myopathy	2021-11-24	criteria provided, single submitter	clinical testing	Variant summary: GNE c.2179G>A (p.Val727Met) results in a conservative amino acid change located in the N-acetylmannosamine kinase domain (UniProt) of 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 0.0017 in 251452 control chromosomes, predominantly at a frequency of 0.013 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 10-fold of the estimated maximal expected allele frequency for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 phenotype (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. However, the variant, c.2179G>A, has also been reported in the literature in numerous compound heterozygous individuals affected with Inclusion Body Myopathy 2 (IBM2) (e.g. Eisenberg_2003, Voermans_2010, Boyden_2011, Cerino_2015, Zhu_2017, Garland_2017, Bhattacharya_2018, Chakravorty_2020), and in some of these reports the variant was noted to segregate with the diseases in the affected families (Boyden_2011, Zhu_2017, Garland_2017). The variant has been reported as a founder mutation in South-East Asian populations, and it is one of the most frequent alleles in Indian patients (see e.g. Bhattacharya_2018, Chakravorty_2020). The variant was also reported in a few homozygous patients (Cerino_2015, Bhattacharya_2018, Chakravorty_2020). However, in at least one of these cases the variant was present on both chromosomes in combination with another variant, thus making this case compound heterozygous; authors of this study concluded that the near absence of homozygous p.Val727Met patients probably suggests that disease may not develop in such individuals (Bhattacharya_2018). A recent genotype-phenotype correlation study concluded that patients carrying the variant, p.Val727Met, appear to have a milder phenotype with later onset (Pogoryelova_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 15 submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, some of them citing overlapping evidence utilized in the context of this evaluation, and classified the variant as pathogenic (n=9), likely pathogenic (n=4), VUS (n=1) or likely benign (n=1). Based on the evidence outlined above, this variant likely represents a hypomorphic allele, which in compound heterozygous state, together with another more severe variant in trans, can cause IBM2 and related phenotypes, however in homozygous form it might not (always) result in disease; therefore, the variant was classified as likely pathogenic.
Mendelics	RCV001167212	SCV002516503	pathogenic	Sialuria	2022-05-04	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000202424	SCV002556429	likely pathogenic	GNE myopathy	2021-05-06	criteria provided, single submitter	clinical testing	This variant has been associated with GNE myopathy when in combination with a pathogenic variant on the other allele. No current reports of affected individuals het or hom for this variant.
Lifecell International Pvt. Ltd	RCV000202424	SCV003925478	pathogenic	GNE myopathy		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.2086G>A in Exon 12 of the GNE gene that results in the amino acid substitution p.Val696Met was identified. The observed variant has a maximum allele frequency of 0.00167/0.00010% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant ID: 430940). This variant was reported among patients for myopathies in the Indian Subcontinent (Chakravorty S et al., 2020). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000202424	SCV004023297	pathogenic	GNE myopathy		criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000202424	SCV004100918	pathogenic	GNE myopathy		criteria provided, single submitter	clinical testing	The missense variant p.V727M in GNE (NM_001128227.2) causes the same amino acid change as a previously established pathogenic variant. It is a founder mutation in the Indian population. There is a small physicochemical difference between valine and methionine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.V727M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The valine residue at codon 727 of GNE is conserved in all mammalian species. The nucleotide c.2179 in GNE is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415667	SCV004116049	pathogenic	GNE-related condition	2023-06-06	criteria provided, single submitter	clinical testing	The GNE c.2179G>A variant is predicted to result in the amino acid substitution p.Val727Met. This variant is also known as c.2086G>A, p.Val696Met using an alternative transcript NM_005476.5. This variant has been reported in many individuals in the compound heterozygous state to be causative for recessive GNE myopathy (Eisenberg et al. 2001. PubMed ID: 11528398; Chaouch et al. 2014. PubMed ID: 24695763; Boyden et al. 2011. PubMed ID: 21708040; Voermans et al. 2010. PubMed ID: 20175955). The c.2179G>A variant has a minor allele frequency of 1.36% in South Asian populations which is consistent with this variant likely being a pathogenic founder mutation in individuals of Indian and Thai descent (Nalini et al. 2013. PubMed ID: 24005727; Tanboon et al. 2014. PubMed ID: 24707269; Voermans et al. 2010. PubMed ID: 20175955). Variants in GNE are also associated with autosomal dominant sialuria (Leroy et al. 2001. PubMed ID: 11326336). Some patients with GNE myopathy were reported to have mild, asymptomatic thrombocytopenia (Mori-Yoshimura et al. 2014. PubMed ID: 25303967). Two recent studies report patients with severe congenital thrombocytopenia with no clinical evidence of GNE myopathy who harbored homozygous variants in GNE (Revel-Vilk et al. 2018. PubMed ID: 30171045; Futterer et al. 2018. PubMed ID: 29941673). In addition to large platelets, patients showed bruising and bleeding tendencies though platelet aggregation appeared to be unaffected. In summary, the c.2179G>A variant is pathogenic for recessive GNE myopathy and may also be associated with other GNE-related conditions.
OMIM	RCV000202424	SCV000026582	pathogenic	GNE myopathy	2001-09-01	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000202424	SCV000238403	pathogenic	GNE myopathy	2014-06-23	no assertion criteria provided	research	This variant (c. 2086G>A; p.V696M) has been previously reported as a pathogenic variant in individuals of Indian and Thai origin. It has been shown to segregate with disease in at least one family, including 3 affected and 4 unaffected individuals (Eisenberg et al 2001; Boyden et al 2011: Liewluck et al 2006; Eisenberg et al 2003).
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000763616	SCV000536694	pathogenic	GNE myopathy; Sialuria	2015-06-15	no assertion criteria provided	research
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000202424	SCV000864132	pathogenic	GNE myopathy	2018-12-04	no assertion criteria provided	clinical testing	The observed variant c.2179G>A (p.V727M) is a known pathogenic variant found very commonly in Indian patients related to GNE Myopathy, has been observed in compound heterozygous status with the other observed variant c.97G>T (p.E33X), which has not been reported in 1000 Genomes and ExAC databases but its in-silico prediction was found to be pathogenic by PolyPhen-2, MutationTaster2 and SIFT.
Counsyl	RCV000202424	SCV001132212	uncertain significance	GNE myopathy	2019-06-13	no assertion criteria provided	clinical testing
Reproductive Health Research and Development, BGI Genomics	RCV000202424	SCV001142396	likely pathogenic	GNE myopathy	2020-01-06	no assertion criteria provided	curation	NM_001128227.2:c.2179G>A in the GNE gene has an allele frequency of 0.013 in South Asian subpopulation in the gnomAD database. This variant has been reported in the compound heterozygous state with p.R160X in a patient with GNE myopathy (PMID: 25182749), and in another four cases in the compound heterozygous state with c. 910G>A, c. 1258C>T, c. 1539G>A, and c. 1703G>T(PMID: 24005727). This variant has been reported to segregate with GNE myopathy in affected families (PMID: 21708040; 28717665; 27829678). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PM3_Strong; PP1_Moderate; PP4.
GeneReviews	RCV000202424	SCV001364095	not provided	GNE myopathy		no assertion provided	literature only