ClinVar Miner

Submissions for variant NM_000302.4(PLOD1):c.1927G>A (p.Val643Ile)

gnomAD frequency: 0.00057  dbSNP: rs149425237
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002310928 SCV000319523 likely benign Familial thoracic aortic aneurysm and aortic dissection 2021-04-27 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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 RCV000311967 SCV000347925 uncertain significance 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000311967 SCV000604866 uncertain significance Ehlers-Danlos syndrome, kyphoscoliotic type 1 2021-05-10 criteria provided, single submitter clinical testing The PLOD1 c.1927G>A; p.Val643Ile variant (rs149425237) is reported in the literature in a family affected with high myopia, though it was not demonstrated to be disease-causing (Kloss 2017). This variant is reported in ClinVar (Variation ID: 263957) and is found in the general population with an overall allele frequency of 0.05% (152/282864 alleles, including one homozygote) in the Genome Aggregation Database. The valine at codon 643 is highly conserved and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.488). However, given the lack of clinical and functional data, the significance of the p.Val643Ile variant is uncertain at this time. References: Kloss BA et al. Exome Sequence Analysis of 14 Families With High Myopia. Invest Ophthalmol Vis Sci. 2017 Apr 1;58(4):1982-1990. PMID: 28384719.
Invitae RCV000311967 SCV000631710 likely benign Ehlers-Danlos syndrome, kyphoscoliotic type 1 2024-01-31 criteria provided, single submitter clinical testing
GeneDx RCV001091324 SCV000714996 likely benign not provided 2020-12-24 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28384719)
CeGaT Center for Human Genetics Tuebingen RCV001091324 SCV001247282 uncertain significance not provided 2019-08-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001091324 SCV001715250 uncertain significance not provided 2023-02-22 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000311967 SCV002495894 uncertain significance Ehlers-Danlos syndrome, kyphoscoliotic type 1 2021-03-08 criteria provided, single submitter clinical testing PLOD1 NM_000302.3 exon 18 p.Val643Ile (c.1927G>A): This variant has been reported in the literature in one individual with high myopia (Kloss 2017 PMID:28384719). However, this variant is also present in 0.1% (75/68026) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-11972896-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:263957). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003479084 SCV004223787 uncertain significance not specified 2023-11-14 criteria provided, single submitter clinical testing Variant summary: PLOD1 c.1927G>A (p.Val643Ile) results in a conservative amino acid change located in the oxoglutarate/iron-dependent dioxygenase domain (IPR005123) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 251478 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in PLOD1 causing Ehlers-Danlos Syndrome Type VI (0.00053 vs 0.0016), allowing no conclusion about variant significance. c.1927G>A has been reported in the literature in at least one family affected with high myopia (Kloss_2017), however 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. The following publication has been ascertained in the context of this evaluation (PMID: 28384719). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; five submitters classified the variant as uncertain significance, while three classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

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