ClinVar Miner

Submissions for variant NM_000302.4(PLOD1):c.1534C>T (p.Arg512Cys) (rs138490756)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000246712 SCV000303545 likely benign not specified criteria provided, single submitter clinical testing
Ambry Genetics RCV000244614 SCV000319413 benign Cardiovascular phenotype 2015-02-04 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000288518 SCV000347876 likely benign Ehlers-Danlos syndrome, hydroxylysine-deficient 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 Praxis fuer Humangenetik Tuebingen RCV000415917 SCV000493164 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing
GeneDx RCV000246712 SCV000589408 likely benign not specified 2017-11-01 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.
Invitae RCV000288518 SCV000631698 likely benign Ehlers-Danlos syndrome, hydroxylysine-deficient 2019-12-31 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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, hydroxylysine-deficient 2019-05-06 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 uncertain significance Ehlers-Danlos syndrome, hydroxylysine-deficient 2018-07-03 criteria provided, single submitter clinical testing The PLOD1 c.1534C>T; p.Arg512Cys variant (rs138490756) has not been reported in the medical literature, but is reported as likely benign by several laboratories in ClinVar (Variation ID: 255801). It is observed in the general population at an overall frequency of 0.33% (905/277004 alleles, 1 homozygote) in the Genome Aggregation Database. The arginine at residue 512 is weakly conserved, but computational algorithms (PolyPhen-2: benign; SIFT: damaging) are inconclusive on the effect of this variant on protein structure and/or function. Although available evidence suggests that p.Arg512Cys may be a rare benign variant, there is insufficient information to determine its clinical significance with certainty. Pathogenic PLOD1 variants are inherited in an autosomal recessive manner, and are associated with Ehlers-Danlos syndrome (EDS), type VI (MIM: 225400). Even if this variant is later determined to be pathogenic, alone, it would not be causative. However, our analysis cannot detect variants in deep intronic or enhancer regions; therefore, the presence of additional pathogenic variants in these regions cannot be excluded. If an additional pathogenic variant, not detected by the current assays, is present on the opposite chromosome, this individual may be affected with EDS.

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