rs121913551
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000302.4(PLOD1):c.2032G>A(p.Gly678Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,460,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G678G) has been classified as Likely benign.
Frequency
Consequence
NM_000302.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLOD1 | ENST00000196061.5 | c.2032G>A | p.Gly678Arg | missense_variant | 19/19 | 1 | NM_000302.4 | ENSP00000196061.4 | ||
PLOD1 | ENST00000481933.1 | n.1459G>A | non_coding_transcript_exon_variant | 2/2 | 2 | |||||
PLOD1 | ENST00000491536.5 | n.384-627G>A | intron_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 152134Hom.: 0 Cov.: 31 FAILED QC
GnomAD3 exomes AF: 0.0000281 AC: 7AN: 249282Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135072
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1460908Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 726732
GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152134Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74322
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, kyphoscoliotic type 1 Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Sep 27, 2022 | ACMG classification criteria: PS4 moderated, PM2 supporting, PM3 strong, PP3 supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 678 of the PLOD1 protein (p.Gly678Arg). This variant is present in population databases (rs121913551, gnomAD 0.02%). This missense change has been observed in individual(s) with Ehlers Danlos syndrome type VI (PMID: 8163671, 21699693). ClinVar contains an entry for this variant (Variation ID: 14366). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PLOD1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PLOD1 function (PMID: 25637337). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 1994 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 26, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at