Submissions for variant NM_182943.3(PLOD2):c.382A>G (p.Lys128Glu)

gnomAD frequency: 0.00056  dbSNP: rs200569129

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000399155	SCV000441491	uncertain significance	Bruck syndrome 2	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.
GeneDx	RCV001591000	SCV001825209	uncertain significance	not provided	2021-04-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patient as a candidate homozygous variant in published literature (Farajzadeh Valilou et al., 2020); This variant is associated with the following publications: (PMID: 32655337)
Invitae	RCV001591000	SCV002280664	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 128 of the PLOD2 protein (p.Lys128Glu). This variant is present in population databases (rs200569129, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of PLOD2-related conditions (PMID: 32655337). ClinVar contains an entry for this variant (Variation ID: 343651). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278537	SCV002564980	uncertain significance	Osteogenesis imperfecta	2020-04-01	criteria provided, single submitter	clinical testing