Submissions for variant NM_020631.5(PLEKHG5):c.2485G>T (p.Asp829Tyr) (rs200162521)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000390391	SCV000358728	likely benign	Distal spinal muscular atrophy, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV000522669	SCV000619856	uncertain significance	not provided	2017-08-11	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the PLEKHG5 gene. The c.2485 G>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D829Y variant is observed in 26/6964 (0.4%) alleles from individuals of East Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.2485 G>T may increase the strength of the cryptic splice acceptor site in exon 20. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.2485 G>T does not alter splicing, it will result in the D829Y missense change, which is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Aspartic Acid are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV001083084	SCV001098336	likely benign	Distal spinal muscular atrophy, autosomal recessive 4; Charcot-Marie-Tooth disease, recessive intermediate c	2020-10-29	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000522669	SCV001549138	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PLEKHG5 p.Asp829Tyr variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs200162521) and in ClinVar (classified as a VUS by GeneDx and Illumina). The variant was also identified in control databases in 61 of 268188 chromosomes at a frequency of 0.000227 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 43 of 19174 chromosomes (freq: 0.002243), South Asian in 14 of 29770 chromosomes (freq: 0.00047), Latino in 1 of 34158 chromosomes (freq: 0.000029) and European (non-Finnish) in 3 of 121270 chromosomes (freq: 0.000025); it was not observed in the African, Ashkenazi Jewish, European (Finnish), and Other populations. The p.Asp829 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 3' splice site. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.