1-11960765-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_000302.4(PLOD1):c.1095C>T(p.Gly365=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000302.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLOD1 | NM_000302.4 | c.1095C>T | p.Gly365= | splice_region_variant, synonymous_variant | 10/19 | ENST00000196061.5 | |
PLOD1 | NM_001316320.2 | c.1236C>T | p.Gly412= | splice_region_variant, synonymous_variant | 11/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLOD1 | ENST00000196061.5 | c.1095C>T | p.Gly365= | splice_region_variant, synonymous_variant | 10/19 | 1 | NM_000302.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152082Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1460644Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5AN XY: 726572
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152082Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74286
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, kyphoscoliotic type 1 Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Sep 27, 2022 | ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderated, PM3 supporting, PP3 supporting - |
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Feb 14, 2023 | The splice region variant c.1095C>T(p.Gly365) variant has been reported in homozygous state in patients affected with Ehlers-Danlos syndrome (Rohrbach M, et. al., 2011; Yan X, et. al., 2022). The variant is reported with an allele frequency of 0% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely pathogenic/ Uncertain Significance. As this variant lies in splice region, additional functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 14, 2023 | This sequence change affects codon 365 of the PLOD1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PLOD1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Ehlers-Danlos syndrome, type VI (EDS VI) (PMID: 10874315, 21699693, 32381727, 35252061). This variant is also known as c.1119C>T. ClinVar contains an entry for this variant (Variation ID: 580535). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 35252061). For these reasons, this variant has been classified as Pathogenic. - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 15, 2023 | The c.1095C>T variant (also known as p.G365G), located in coding exon 10 of the PLOD1 gene, results from a C to T substitution at nucleotide position 1095. This nucleotide substitution does not change the at codon 365. This alteration, which is also known as c.1119C>T, has been reported as homozygous in an individuals with concerns for autosomal recessive kyphoscoliotic Ehlers-Danlos syndrome (EDS type VI) (Rohrbach M et al. Orphanet J Rare Dis, 2011 Jun;6:46; Zhao S et al. J Med Genet, 2021 Jan;58:41-47; Yan X et al. Front Pediatr, 2022 Feb;10:813758). Additionally, this alteration has been noted with a second PLOD1 alteration (phase unknown) in another individual with a clinical diagnosis of EDS type VI (Yeowell HN et al. Hum Mutat, 2000 Jul;16:90). RNA studies showed complete aberrant splicing (Yan X et al. Front Pediatr, 2022 Feb;10:813758). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 03, 2019 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includessplice predictorsand evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10686424, 21699693, 10874315) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at