Submissions for variant NM_000302.4(PLOD1):c.1495C>T (p.Arg499Trp)

gnomAD frequency: 0.00030  dbSNP: rs149124387

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000382781	SCV000347875	likely benign	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 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.
Invitae	RCV000382781	SCV000631695	likely benign	Ehlers-Danlos syndrome, kyphoscoliotic type 1	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002314038	SCV000739546	benign	Familial thoracic aortic aneurysm and aortic dissection	2017-10-23	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.
GeneDx	RCV000839243	SCV000981130	likely benign	not provided	2018-06-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CeGaT Center for Human Genetics Tuebingen	RCV000839243	SCV004700626	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	PLOD1: BS2
PreventionGenetics, part of Exact Sciences	RCV003957530	SCV004769517	likely benign	PLOD1-related condition	2019-07-30	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987497	SCV004804404	likely benign	not specified	2024-01-02	criteria provided, single submitter	clinical testing	Variant summary: PLOD1 c.1495C>T (p.Arg499Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00083 in 251170 control chromosomes, predominantly at a frequency of 0.0064 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4.048 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 East Asian origin. c.1495C>T has been reported in the literature in individuals affected with TAD who also carried a pathogenic FBN1 variant (Gago-Diaz_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Ehlers-Danlos Syndrome Type VI. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.