Submissions for variant NM_000302.4(PLOD1):c.1203-3C>T

gnomAD frequency: 0.00009  dbSNP: rs376288573

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000529461	SCV000631690	uncertain significance	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change falls in intron 11 of the PLOD1 gene. It does not directly 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 (rs376288573, 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: 459805). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000585087	SCV000692603	uncertain significance	not provided	2017-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000585087	SCV000732426	likely benign	not provided	2021-04-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002314962	SCV000739527	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-23	criteria provided, single submitter	clinical testing	The c.1203-3C>T intronic variant results from a C to T substitution 3 nucleotides upstream from coding exon 12 in the PLOD1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV000529461	SCV001257340	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000529461	SCV001474038	likely benign	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2019-12-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000529461	SCV003811184	uncertain significance	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2019-05-02	criteria provided, single submitter	clinical testing