ClinVar Miner

Submissions for variant NM_005476.7(GNE):c.647T>C (p.Val216Ala)

gnomAD frequency: 0.00004  dbSNP: rs779694939
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255797 SCV000321741 pathogenic not provided 2022-06-01 criteria provided, single submitter clinical testing Functional studies have shown that the V216A variant reduces GNE enzyme activity (Sparks et al., 2005).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24695763, 19917666, 33214394, 30564623, 15987957, 14972325, 25002140, 12473769)
Eurofins Ntd Llc (ga) RCV000255797 SCV000339268 likely pathogenic not provided 2016-03-16 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000255797 SCV000613536 pathogenic not provided 2017-01-24 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000627756 SCV000638336 pathogenic GNE myopathy; Sialuria 2024-07-29 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 247 of the GNE protein (p.Val247Ala). This variant is present in population databases (rs779694939, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive myopathy (PMID: 12473769, 24136589, 24695763). 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.Val216Ala. ClinVar contains an entry for this variant (Variation ID: 218297). 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. Experimental studies have shown that this missense change affects GNE function (PMID: 15987957). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000202427 SCV000789772 likely pathogenic GNE myopathy 2017-02-17 criteria provided, single submitter clinical testing
Baylor Genetics RCV000627756 SCV001163613 likely pathogenic GNE myopathy; Sialuria criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000202427 SCV002572205 pathogenic GNE myopathy 2022-08-21 criteria provided, single submitter clinical testing Variant summary: GNE c.740T>C (p.Val247Ala) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of 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 2.4e-05 in 251348 control chromosomes. c.740T>C has been reported in the literature in individuals affected with Inclusion Body Myopathy 2 (example, Vasconcelos_2002, Gottileb_2005, Chaouch_2014, Patzel_2014, Chrisman_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Sparks_2005). The most pronounced variant effect results in <2% of normal epimerase activity in-vitro. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005003557 SCV002791544 likely pathogenic GNE myopathy; Sialuria; Thrombocytopenia 12 with or without myopathy 2024-01-15 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000255797 SCV003828614 likely pathogenic not provided 2022-06-25 criteria provided, single submitter clinical testing
Baylor Genetics RCV000202427 SCV004199383 likely pathogenic GNE myopathy 2024-01-16 criteria provided, single submitter clinical testing
OMIM RCV000202427 SCV000257487 pathogenic GNE myopathy 2002-12-10 no assertion criteria provided literature only
Natera, Inc. RCV000202427 SCV001458440 pathogenic GNE myopathy 2020-09-16 no assertion criteria provided clinical testing

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