ClinVar Miner

Submissions for variant NM_000302.4(PLOD1):c.1651-2A>G

gnomAD frequency: 0.00004  dbSNP: rs565513365
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254922 SCV000322475 pathogenic not provided 2022-09-01 criteria provided, single submitter clinical testing Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 21699693)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002397 SCV001160318 pathogenic Ehlers-Danlos syndrome, kyphoscoliotic type 1 2019-02-20 criteria provided, single submitter clinical testing The c.1651-2A>G variant has been previously identified in the homozygous state in an individual reported to be affected with kyphoscoliotic type Ehlers-Danlos syndrome (Rohrbach. 2011) This variant is found in the non-Finnish European allele frequency of 0.008 % (10/ 126,640 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice acceptor site of intron 15, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic.
Invitae RCV001002397 SCV001578250 pathogenic Ehlers-Danlos syndrome, kyphoscoliotic type 1 2023-12-02 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 15 of the PLOD1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs565513365, gnomAD 0.008%). Disruption of this splice site has been observed in individual(s) with Ehlers-Danlos syndrome, kyphoscoliotic form (PMID: 21699693). ClinVar contains an entry for this variant (Variation ID: 265507). Studies have shown that disruption of this splice site results in skipping of exon 16, but is expected to preserve the integrity of the reading-frame (PMID: 9450904). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002401967 SCV002704667 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2018-03-26 criteria provided, single submitter clinical testing The c.1651-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 16 in the PLOD1 gene. This alteration has been reported as homozygous in a child with the autosomal recessive kyphoscoliotic type of Ehlers-Danlos syndrome (kEDS), which was previously described as EDS-VIA (Rohrbach M et al. Orphanet J Rare Dis, 2011 Jun;6:46). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000254922 SCV001744585 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000254922 SCV001807298 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000254922 SCV001966652 likely pathogenic not provided no assertion criteria provided clinical testing

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