Submissions for variant NM_000302.4(PLOD1):c.1533C>G (p.Tyr511Ter)

gnomAD frequency: 0.00002  dbSNP: rs121913552

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255839	SCV000322474	pathogenic	not provided	2023-06-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Functional studies performed on patient fibroblasts demonstrated this variant may result in exon skipping, which results in a truncated protein product missing the 38 amino acids encoded by exon 14, and results in significantly reduced lysyl hydroxylase activity (Walker et al., 1999; Pousi et al., 2000; Yeowell et al., 2000); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20301635, 25525159, 9220536, 10329027, 10729709, 10874315, 31345219)
Invitae	RCV000015447	SCV000631697	pathogenic	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr511*) in the PLOD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PLOD1 are known to be pathogenic (PMID: 10874315, 21699693). This variant is present in population databases (rs121913552, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with Ehlers-Danlos syndrome type VI (PMID: 9220536, 10329027). ClinVar contains an entry for this variant (Variation ID: 14370). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002313712	SCV000739556	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-10-19	criteria provided, single submitter	clinical testing	The p.Y511* pathogenic mutation (also known as c.1533C>G), located in coding exon 14 of the PLOD1 gene, results from a C to G substitution at nucleotide position 1533. This changes the amino acid from a tyrosine to a stop codon within coding exon 14. This alteration has been reported in patients with kyphoscoliotic Ehlers-Danlos syndrome (Yeowell HN et al. Proc. Assoc. Am. Physicians, 1997 Jul;109:383-96; Walker LC et al. Mol. Genet. Metab., 1999 May;67:74-82). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV000015447	SCV000807212	pathogenic	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2017-09-01	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory in trans with a pathogenic variant in a 4-year-old female with tall habitus, hyperextensibility, hip dysplasia, mild scoliosis, lumbar kyphosis, arachnodactyly, fragile connective tissue, motor delays, hypotonia, dysmorphisms, tethered cord, eye anomalies
Revvity Omics, Revvity	RCV000015447	SCV002018860	pathogenic	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2020-03-24	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276550	SCV002566013	pathogenic	Ehlers-Danlos syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000255839	SCV004226711	pathogenic	not provided	2022-07-19	criteria provided, single submitter	clinical testing	PP4, PM3_strong, PS3, PS4, PVS1
PreventionGenetics, part of Exact Sciences	RCV003904842	SCV004719212	pathogenic	PLOD1-related condition	2023-11-15	criteria provided, single submitter	clinical testing	The PLOD1 c.1533C>G variant is predicted to result in premature protein termination (p.Tyr511*). This variant was reported, along with another pathogenic variant, in an individual with Ehlers-Danlos syndrome VI (Yeowell et al. 1997. PubMed ID: 9220536). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-12025599-C-G). Nonsense variants in PLOD1 are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000015447	SCV000035712	pathogenic	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2000-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000015447	SCV002567825	not provided	Ehlers-Danlos syndrome, kyphoscoliotic type 1		no assertion provided	literature only