chr1-11964188-C-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000302.4(PLOD1):āc.1216C>Gā(p.Pro406Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,688 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 Uncertain significance (ā ā ).
Frequency
Genomes: not found (cov: 29)
Exomes š: 0.0000021 ( 0 hom. )
Consequence
PLOD1
NM_000302.4 missense
NM_000302.4 missense
Scores
12
5
2
Clinical Significance
Conservation
PhyloP100: 7.80
Genes affected
PLOD1 (HGNC:9081): (procollagen-lysine,2-oxoglutarate 5-dioxygenase 1) Lysyl hydroxylase is a membrane-bound homodimeric protein localized to the cisternae of the endoplasmic reticulum. The enzyme (cofactors iron and ascorbate) catalyzes the hydroxylation of lysyl residues in collagen-like peptides. The resultant hydroxylysyl groups are attachment sites for carbohydrates in collagen and thus are critical for the stability of intermolecular crosslinks. Some patients with Ehlers-Danlos syndrome type VI have deficiencies in lysyl hydroxylase activity. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.964
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PLOD1 | NM_000302.4 | c.1216C>G | p.Pro406Ala | missense_variant | 12/19 | ENST00000196061.5 | NP_000293.2 | |
PLOD1 | NM_001316320.2 | c.1357C>G | p.Pro453Ala | missense_variant | 13/20 | NP_001303249.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLOD1 | ENST00000196061.5 | c.1216C>G | p.Pro406Ala | missense_variant | 12/19 | 1 | NM_000302.4 | ENSP00000196061 | P1 |
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD3 genomes
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29
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251336Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135838
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461688Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2AN XY: 727134
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GnomAD4 genome Cov.: 29
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 07, 2023 | The p.P406A variant (also known as c.1216C>G), located in coding exon 12 of the PLOD1 gene, results from a C to G substitution at nucleotide position 1216. The proline at codon 406 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Ehlers-Danlos syndrome, kyphoscoliotic type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 01, 2021 | This sequence change replaces proline with alanine at codon 406 of the PLOD1 protein (p.Pro406Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs760764359, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with PLOD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 520125). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at