ClinVar Miner

Submissions for variant NM_006158.5(NEFL):c.64C>T (p.Pro22Ser)

dbSNP: rs28928910
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000415401 SCV000493018 likely pathogenic Pes cavus; Distal lower limb muscle weakness; Peripheral neuropathy 2014-06-03 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000414916 SCV000493036 pathogenic Decreased nerve conduction velocity; Distal muscle weakness; Hand muscle atrophy; Peripheral demyelination; Peripheral neuropathy 2014-06-11 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001196666 SCV001367296 pathogenic Charcot-Marie-Tooth disease type 1F 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic.
Invitae RCV000015073 SCV001377432 pathogenic Charcot-Marie-Tooth disease type 2E 2022-09-01 criteria provided, single submitter clinical testing This missense change has been observed in individuals with mixed axonal and demyelinating neuropathy (PMID: 12481988, 15111691, 19286384). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NEFL function (PMID: 16452125, 21168446). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 14029). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 22 of the NEFL protein (p.Pro22Ser).
Ambry Genetics RCV002362585 SCV002659258 pathogenic Inborn genetic diseases 2022-02-18 criteria provided, single submitter clinical testing The p.P22S pathogenic mutation (also known as c.64C>T), located in coding exon 1 of the NEFL gene, results from a C to T substitution at nucleotide position 64. The proline at codon 22 is replaced by serine, an amino acid with similar properties. This variant was found to segregate with autosomal dominant Charcot-Marie-Tooth disease in one multigenerational family (Georgiou DM et al. Neurogenetics, 2002 Oct;4:93-6). This alteration has also been detected in the heterozygous state in individuals with mixed demyelinating and axonal neuropathy (Fabrizi GM et al. Neurology, 2004 Apr;62:1429-31; Bhagavati S et al. J Clin Neurosci, 2009 Jun;16:830-1). Functional studies have shown that this alteration led to abnormal neurofilament assembly and recapitulates the neuropathy phenotype in a mouse model (Fabrizi GM et al. Neurology, 2004 Apr;62:1429-31; Dequen F et al. Hum Mol Genet, 2010 Jul;19:2616-29; Miao L et al. J Cell Sci, 2013 Jan;126:427-36; Stone EJ et al. Cytoskeleton (Hoboken), 2019 07;76:423-439). Based on the supporting evidence, this variant is expected to be causative of Charcot-Marie-Tooth (CMT) disease, type 1F/2E; however, its clinical significance for the autosomal recessive form of NEFL-related CMT is unclear.
Athena Diagnostics Inc RCV000057144 SCV004229812 pathogenic not provided 2022-12-20 criteria provided, single submitter clinical testing This variant segregates with autosomal dominant CMT in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 16452125, 23230147, 20421365, 21168446)
OMIM RCV000015073 SCV000035329 pathogenic Charcot-Marie-Tooth disease type 2E 2006-03-15 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057144 SCV000088257 not provided not provided no assertion provided not provided
GeneReviews RCV000194357 SCV000243953 not provided Charcot-Marie-Tooth disease type 1C no assertion provided literature only

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