rs149425237
Variant summary
Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1
The NM_000302.4(PLOD1):c.1927G>A(p.Val643Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000914 in 1,613,980 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V643V) has been classified as Likely benign.
Frequency
Consequence
NM_000302.4 missense
Scores
Clinical Significance
Conservation
Publications
- Ehlers-Danlos syndrome, kyphoscoliotic type 1Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, PanelApp Australia, G2P
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ACMG classification
Our verdict: Benign. The variant received -7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLOD1 | ENST00000196061.5 | c.1927G>A | p.Val643Ile | missense_variant | Exon 18 of 19 | 1 | NM_000302.4 | ENSP00000196061.4 | ||
PLOD1 | ENST00000481933.1 | n.1354G>A | non_coding_transcript_exon_variant | Exon 1 of 2 | 2 | |||||
PLOD1 | ENST00000491536.5 | n.384-2387G>A | intron_variant | Intron 4 of 4 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000690 AC: 105AN: 152074Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.000533 AC: 134AN: 251478 AF XY: 0.000574 show subpopulations
GnomAD4 exome AF: 0.000937 AC: 1370AN: 1461788Hom.: 1 Cov.: 31 AF XY: 0.000897 AC XY: 652AN XY: 727208 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000690 AC: 105AN: 152192Hom.: 0 Cov.: 31 AF XY: 0.000591 AC XY: 44AN XY: 74388 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, kyphoscoliotic type 1 Uncertain:3Benign:1
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. -
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. -
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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. -
not provided Uncertain:1Benign:2
This variant is associated with the following publications: (PMID: 28384719) -
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PLOD1: PP3, BS2 -
not specified Uncertain:1
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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00091 in 1613980 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in PLOD1 causing Ehlers-Danlos Syndrome Type VI (0.00091 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) and an individual with pediatric myoamoya angiopathy who also had a pathogenic varinat in NF1 (Zanoni_2023), however these report(s) do not provide unequivocal conclusions about association of the variant with Ehlers-Danlos Syndrome Type VI. Co-occurrences with other pathogenic variant(s) have been reported (NF1 c.4971_4977del, p.(Tyr1657*)), providing supporting evidence for a benign role (Zanoni_2023). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28384719, 37012328). ClinVar contains an entry for this variant (Variation ID: 263957). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Cardiovascular phenotype Uncertain:1
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Familial thoracic aortic aneurysm and aortic dissection Benign:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at