ClinVar Miner

Submissions for variant NM_000302.4(PLOD1):c.1095C>T (p.Gly365=)

gnomAD frequency: 0.00001  dbSNP: rs1032781250
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000704105 SCV000833040 pathogenic Ehlers-Danlos syndrome, kyphoscoliotic type 1 2023-10-14 criteria provided, single submitter clinical testing This sequence change affects codon 365 of the PLOD1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PLOD1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Ehlers-Danlos syndrome, type VI (EDS VI) (PMID: 10874315, 21699693, 32381727, 35252061). This variant is also known as c.1119C>T. ClinVar contains an entry for this variant (Variation ID: 580535). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 35252061). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001759409 SCV001986249 uncertain significance not provided 2019-07-03 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includessplice predictorsand evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10686424, 21699693, 10874315)
Ambry Genetics RCV002458301 SCV002737016 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2023-02-15 criteria provided, single submitter clinical testing The c.1095C>T variant (also known as p.G365G), located in coding exon 10 of the PLOD1 gene, results from a C to T substitution at nucleotide position 1095. This nucleotide substitution does not change the at codon 365. This alteration, which is also known as c.1119C>T, has been reported as homozygous in an individuals with concerns for autosomal recessive kyphoscoliotic Ehlers-Danlos syndrome (EDS type VI) (Rohrbach M et al. Orphanet J Rare Dis, 2011 Jun;6:46; Zhao S et al. J Med Genet, 2021 Jan;58:41-47; Yan X et al. Front Pediatr, 2022 Feb;10:813758). Additionally, this alteration has been noted with a second PLOD1 alteration (phase unknown) in another individual with a clinical diagnosis of EDS type VI (Yeowell HN et al. Hum Mutat, 2000 Jul;16:90). RNA studies showed complete aberrant splicing (Yan X et al. Front Pediatr, 2022 Feb;10:813758). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000704105 SCV003807522 likely pathogenic Ehlers-Danlos syndrome, kyphoscoliotic type 1 2022-09-27 criteria provided, single submitter clinical testing ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderated, PM3 supporting, PP3 supporting
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV000704105 SCV004176556 uncertain significance Ehlers-Danlos syndrome, kyphoscoliotic type 1 2023-02-14 criteria provided, single submitter clinical testing The splice region variant c.1095C>T(p.Gly365) variant has been reported in homozygous state in patients affected with Ehlers-Danlos syndrome (Rohrbach M, et. al., 2011; Yan X, et. al., 2022). The variant is reported with an allele frequency of 0% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely pathogenic/ Uncertain Significance. As this variant lies in splice region, additional functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS)

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