rs121913552
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000302.4(PLOD1):āc.1533C>Gā(p.Tyr511*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,613,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000302.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PLOD1 | NM_000302.4 | c.1533C>G | p.Tyr511* | stop_gained | 14/19 | ENST00000196061.5 | NP_000293.2 | |
PLOD1 | NM_001316320.2 | c.1674C>G | p.Tyr558* | stop_gained | 15/20 | NP_001303249.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLOD1 | ENST00000196061.5 | c.1533C>G | p.Tyr511* | stop_gained | 14/19 | 1 | NM_000302.4 | ENSP00000196061.4 | ||
PLOD1 | ENST00000470133.1 | n.147C>G | non_coding_transcript_exon_variant | 2/3 | 3 | |||||
PLOD1 | ENST00000491536.5 | n.161C>G | non_coding_transcript_exon_variant | 2/5 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152154Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251214Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135844
GnomAD4 exome AF: 0.000129 AC: 188AN: 1461466Hom.: 0 Cov.: 31 AF XY: 0.000120 AC XY: 87AN XY: 727036
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152154Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74332
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, kyphoscoliotic type 1 Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This variant has been previously reported as disease-causing and was found once in our laboratory in trans with a pathogenic variant in a 4-year-old female with tall habitus, hyperextensibility, hip dysplasia, mild scoliosis, lumbar kyphosis, arachnodactyly, fragile connective tissue, motor delays, hypotonia, dysmorphisms, tethered cord, eye anomalies - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 03, 2024 | This sequence change creates a premature translational stop signal (p.Tyr511*) in the PLOD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PLOD1 are known to be pathogenic (PMID: 10874315, 21699693). This variant is present in population databases (rs121913552, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with Ehlers-Danlos syndrome type VI (PMID: 9220536, 10329027). ClinVar contains an entry for this variant (Variation ID: 14370). For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2000 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 24, 2020 | - - |
Ehlers-Danlos syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 16, 2019 | The p.Tyr511X variant in PLOD1 has been reported in 2 homozygous and 2 compound heterozygous individuals with Ehlers-Danlos syndrome type VI (Walker 1999, Yeowell and Walker 1997, Yeowell 2000). It has also been identified in 2/128944 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID 14370). This nonsense variant leads to a premature termination codon at position 511, which is predicted to lead to a truncated or absent protein. Loss of function of the PLOD1 gene is strongly associated with autosomal recessive Ehlers-Danlos syndrome type VI. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Ehlers-Danlos syndrome type VI. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong, PM2_Supporting. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Functional studies performed on patient fibroblasts demonstrated this variant may result in exon skipping, which results in a truncated protein product missing the 38 amino acids encoded by exon 14, and results in significantly reduced lysyl hydroxylase activity (Walker et al., 1999; Pousi et al., 2000; Yeowell et al., 2000); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20301635, 25525159, 9220536, 10329027, 10729709, 10874315, 31345219) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 19, 2022 | PP4, PM3_strong, PS3, PS4, PVS1 - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 12, 2024 | The p.Y511* pathogenic mutation (also known as c.1533C>G), located in coding exon 14 of the PLOD1 gene, results from a C to G substitution at nucleotide position 1533. This changes the amino acid from a tyrosine to a stop codon within coding exon 14. This alteration has been reported in patients with kyphoscoliotic Ehlers-Danlos syndrome (Yeowell HN et al. Proc. Assoc. Am. Physicians, 1997 Jul;109:383-96; Walker LC et al. Mol. Genet. Metab., 1999 May;67:74-82). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
PLOD1-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 24, 2024 | The PLOD1 c.1533C>G variant is predicted to result in premature protein termination (p.Tyr511*). This variant was reported, along with another pathogenic variant, in an individual with Ehlers-Danlos syndrome VI (Yeowell et al. 1997. PubMed ID: 9220536). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. Nonsense variants in PLOD1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at