Submissions for variant NM_198681.4(PLEKHG5):c.-120C>T

dbSNP: rs201669114

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mayo Clinic Laboratories, Mayo Clinic	RCV001357159	SCV001712957	uncertain significance	not provided	2022-04-13	criteria provided, single submitter	clinical testing	BP4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001357159	SCV002050196	uncertain significance	not provided	2021-08-20	criteria provided, single submitter	clinical testing	The PLEKHG5 c.112C>T, p.Pro38Ser (rs201669114), is reported in the literature in 4 individuals in 2 families affected with Alzheimer’s disease (Cukier, 2017), but has not been reported in patients affected with Charcot-Marie-Tooth disease. This variant is found in the general population with an allele frequency of 0.13% (362/271,658 alleles, including 1 homozygote) in the Genome Aggregation Database. The proline at codon 38 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the clinical significance of this variant is uncertain at this time.
CeGaT Center for Human Genetics Tuebingen	RCV001357159	SCV004042413	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PLEKHG5: BP4
PreventionGenetics, part of Exact Sciences	RCV003918882	SCV004739688	likely benign	PLEKHG5-related condition	2020-08-13	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357159	SCV001552531	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PLEKHG5 p.Pro40Ser variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs201669114) and in control databases in 362 of 271658 chromosomes (1 homozygous) at a frequency of 0.001333 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 304 of 123808 chromosomes (freq: 0.002455), Ashkenazi Jewish in 17 of 10068 chromosomes (freq: 0.001689), Other in 7 of 6866 chromosomes (freq: 0.00102), Latino in 19 of 34140 chromosomes (freq: 0.000557), European (Finnish) in 8 of 24888 chromosomes (freq: 0.000321), African in 6 of 23608 chromosomes (freq: 0.000254) and South Asian in 1 of 29698 chromosomes (freq: 0.000034), but was not observed in the East Asian population. The p.Pro40 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.
Institute of Human Genetics, University of Wuerzburg	RCV002271226	SCV002553214	uncertain significance	Peripheral neuropathy		no assertion criteria provided	clinical testing