ClinVar Miner

Submissions for variant NM_005476.7(GNE):c.2086G>A (p.Val696Met) (rs121908627)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255973 SCV000700541 pathogenic not provided 2018-04-13 criteria provided, single submitter clinical testing
Foundation for Research in Genetics and Endocrinology,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.
Fulgent Genetics,Fulgent Genetics RCV000763616 SCV000894470 likely pathogenic GNE myopathy; Sialuria 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000255973 SCV000321744 pathogenic not provided 2018-05-31 criteria provided, single submitter clinical testing The V727M pathogenic variant in the GNE gene has been reported, using alternative nomenclature, in multiple individuals with GNE myopathy who harbored a pathogenic variant on the opposite GNE allele (Eisenberg et al., 2001; Boyden et al., 2011). Additionally, the V727M variant has been observed in multiple individuals with myopathy who harbored a second pathogenic GNE variant, although it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Liewluck et al., 2006; de Dios et al., 2014; Voerrmans et al., 2010). The V727M variant has been reported as a founder mutation in South-East Asian populations (Nishino et al., 2014). The V727M variant is observed in 418/30,782 (1.36%) alleles from individuals of South Asian background (Lek et al., 2016). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. We interpret V727M as a pathogenic variant.
GenePathDx,Causeway Health Care Private Ltd 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 likely pathogenic GNE myopathy; Sialuria 2018-05-08 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 727 of the GNE protein (p.Val727Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs121908627, ExAC 1.4%). This variant has been reported in the compound heterozygous state in many individuals affected with GNE myopathy/distal myopathy with rimmed vacuoles (PMID: 25182749, 20175955, 24005727, 11528398, 12497639, 23437777). In addition, this variant has been reported to segregate with GNE myopathy in affected families (PMID: 21708040, 28717665, 27829678). This variant is also known as p.Val696Met in the literature. ClinVar contains an entry for this variant (Variation ID: 6028). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a missense change that has been reported in many affected individuals and has been observed to segregate with GNE myopathy in an affected family. It has been referred to as a commonly causative variant in the south asian population (PMID: 23549799, 25002140, 24796702), but it also occurs at relatively high frequency in this population. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000202424 SCV000026582 pathogenic GNE myopathy 2001-09-01 no assertion criteria provided literature only

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