Submissions for variant NM_000302.4(PLOD1):c.1534C>T (p.Arg512Cys)

gnomAD frequency: 0.00328  dbSNP: rs138490756

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000246712	SCV000303545	likely benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002310826	SCV000319413	benign	Familial thoracic aortic aneurysm and aortic dissection	2015-02-04	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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	RCV000288518	SCV000347876	likely benign	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2018-01-12	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000415917	SCV000493164	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	PLOD1: BP4, BS2
GeneDx	RCV000415917	SCV000589408	likely benign	not provided	2021-06-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16758144, 14565595)
Invitae	RCV000288518	SCV000631698	likely benign	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000246712	SCV000703499	likely benign	not specified	2016-12-19	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000288518	SCV000898886	uncertain significance	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2021-03-30	criteria provided, single submitter	clinical testing	PLOD1 NM_000302.3 exon 14 p.Arg512Cys (c.1534C>T): This variant has not been reported in the literature, but it is present in 0.5% (653/126532) of European alleles, including one homozygote, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-12025600-C-T). This variant is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID: 255801). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant are insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000288518	SCV001156785	likely benign	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2023-10-03	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277608	SCV002566014	benign	Ehlers-Danlos syndrome	2021-07-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000246712	SCV004039141	likely benign	not specified	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: PLOD1 c.1534C>T (p.Arg512Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 251210 control chromosomes, predominantly at a frequency of 0.0049 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PLOD1 causing Ehlers-Danlos Syndrome Type VI phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1534C>T in individuals affected with Ehlers-Danlos Syndrome Type VI and no experimental evidence demonstrating its impact on protein function have been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=8) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign.