Submissions for variant NM_000302.4(PLOD1):c.303C>T (p.Ser101=)

gnomAD frequency: 0.00013  dbSNP: rs147980436

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000547593	SCV000604865	uncertain significance	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2024-04-04	criteria provided, single submitter	clinical testing	The PLOD1 c.303C>T; p.Ser101= variant (rs147980436), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 440168).This variant is found in the non-Finnish European population with an allele frequency of 0.03% (42/127636 alleles) in the Genome Aggregation Database (v2.1.1). This is a synonymous variant and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant does not alter splicing. However, since this variant is located within the minimal splice region, the clinical significance of this variant is uncertain at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547593	SCV000631720	uncertain significance	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change affects codon 101 of the PLOD1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PLOD1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs147980436, gnomAD 0.03%). 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: 440168). 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.
GeneDx	RCV000507622	SCV000726603	likely benign	not specified	2018-01-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV002314889	SCV000739532	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2023-07-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000547593	SCV001257525	uncertain significance	Ehlers-Danlos syndrome, kyphoscoliotic type 1	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.
CeGaT Center for Human Genetics Tuebingen	RCV001312061	SCV001502495	likely benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	PLOD1: BP4, BP7
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000507622	SCV005077613	uncertain significance	not specified	2024-04-17	criteria provided, single submitter	clinical testing	Variant summary: PLOD1 c.303C>T (p.Ser101Ser) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00016 in 249698 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PLOD1 causing Ehlers-Danlos Syndrome Type VI (0.00016 vs 0.0016), allowing no conclusion about variant significance. To our knowledge, c.303C>T has not been reported in the literature in individuals affected with Ehlers-Danlos Syndrome Type VI and no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 440168). Based on the evidence outlined above, the variant was classified as uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001312061	SCV001742623	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001312061	SCV001807493	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001312061	SCV001927592	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001312061	SCV001951102	likely benign	not provided		no assertion criteria provided	clinical testing