Submissions for variant NM_000302.4(PLOD1):c.614G>A (p.Arg205His)

gnomAD frequency: 0.00004  dbSNP: rs536503346

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000377885	SCV000347855	uncertain significance	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2018-01-12	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	RCV000522057	SCV000621679	uncertain significance	not provided	2022-03-02	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Invitae	RCV000377885	SCV001508692	uncertain significance	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2022-07-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 205 of the PLOD1 protein (p.Arg205His). This variant is present in population databases (rs536503346, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PLOD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 292287). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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	RCV002356402	SCV002660288	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-07-06	criteria provided, single submitter	clinical testing	The p.R205H variant (also known as c.614G>A), located in coding exon 6 of the PLOD1 gene, results from a G to A substitution at nucleotide position 614. The arginine at codon 205 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.