Submissions for variant NM_020631.6(PLEKHG5):c.2249+4C>T

gnomAD frequency: 0.00001  dbSNP: rs751575330

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001093788	SCV000358737	uncertain significance	Neuronopathy, distal hereditary motor, autosomal recessive 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001362746	SCV001558779	uncertain significance	Neuronopathy, distal hereditary motor, autosomal recessive 4; Charcot-Marie-Tooth disease recessive intermediate C	2022-08-10	criteria provided, single submitter	clinical testing	This sequence change falls in intron 19 of the PLEKHG5 gene. It does not directly change the encoded amino acid sequence of the PLEKHG5 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs751575330, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PLEKHG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 297947). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002429251	SCV002731043	uncertain significance	Inborn genetic diseases	2022-05-11	criteria provided, single submitter	clinical testing	The c.2249+4C>T intronic variant results from a C to T substitution 4 nucleotides after coding exon 18 in the PLEKHG5 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Institute of Human Genetics, Cologne University	RCV000268467	SCV000787821	uncertain significance	Distal spinal muscular atrophy	2018-04-26	no assertion criteria provided	clinical testing