rs149161535
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_000302.4(PLOD1):c.2162C>T(p.Ala721Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A721T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000302.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLOD1 | NM_000302.4 | c.2162C>T | p.Ala721Val | missense_variant | 19/19 | ENST00000196061.5 | |
PLOD1 | NM_001316320.2 | c.2303C>T | p.Ala768Val | missense_variant | 20/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLOD1 | ENST00000196061.5 | c.2162C>T | p.Ala721Val | missense_variant | 19/19 | 1 | NM_000302.4 | P1 | |
PLOD1 | ENST00000481933.1 | n.1589C>T | non_coding_transcript_exon_variant | 2/2 | 2 | ||||
PLOD1 | ENST00000491536.5 | n.384-497C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152194Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251402Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135916
GnomAD4 exome AF: 0.0000657 AC: 96AN: 1461852Hom.: 0 Cov.: 31 AF XY: 0.0000509 AC XY: 37AN XY: 727228
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152194Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5AN XY: 74342
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 28, 2016 | A variant of uncertain significance has been identified in the PLOD1 gene. The A721V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed at a significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the A721V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Alanine are tolerated across species, and Valine is the wild-type amino acid at this position in at least one species. Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 16, 2023 | The p.A721V variant (also known as c.2162C>T), located in coding exon 19 of the PLOD1 gene, results from a C to T substitution at nucleotide position 2162. The alanine at codon 721 is replaced by valine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, valine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 | Invitae | Jul 04, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 721 of the PLOD1 protein (p.Ala721Val). This variant is present in population databases (rs149161535, gnomAD 0.006%). 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: 373603). 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 tolerated. 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at