rs377658203
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_014908.4(DOLK):c.560G>T(p.Arg187Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,830 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R187H) has been classified as Uncertain significance.
Frequency
Consequence
NM_014908.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DOLK | NM_014908.4 | c.560G>T | p.Arg187Leu | missense_variant | 1/1 | ENST00000372586.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DOLK | ENST00000372586.4 | c.560G>T | p.Arg187Leu | missense_variant | 1/1 | NM_014908.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151976Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251196Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135784
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461854Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727226
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151976Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74222
ClinVar
Submissions by phenotype
DK1-congenital disorder of glycosylation Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 10, 2022 | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 187 of the DOLK protein (p.Arg187Leu). This variant is present in population databases (rs377658203, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with DOLK-related conditions. ClinVar contains an entry for this variant (Variation ID: 532844). 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. - |
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Oct 25, 2017 | Found in a Caucasian teenager with a new diagnosis of HCM and a long history of prolonged QTc intervals. He had a 130-gene Arrhythmia and Cardiomyopathy Comprehensive Panel with the Invitae laboratory. Results showed 4 variants: -p.Arg187Leu (c.560G>T) in the DOLK gene -p.Leu691Phe (c.2071C>T) in the DSP gene -p.Gly1546Ser (c.4636G>A) in the FLNC gene -p.Arg216Gln (c.647G>A) in the JUP gene p.Arg187Leu (c.560G>T) in exon 1 of the DOLK gene (NM_014908.3) Chromosome location 9:131709023 C / A Based on the information reviewed below, we classify this as a Variant of Uncertain Significance, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has not previously been reported in the literature in association with disease, according to the Invitae report. The DOLK gene is associated with the autosomal recessive congenital disorder of glycosylation DOLK-CDG (CDG-Im) (MedGen UID 332072). The clinical significance of this variant is uncertain at this time, although because DOLK-CDG is autosomal recessive, any single variant is likely insufficient as an explanation for disease. This is a nonconservative acid change, resulting in the replacement of a positively-charged Arginine with a nonpolar Leucine. Arginine at this location is very highly conserved across ~100 vertebrate species for which we have data (it is a Cysteine in one species of bat). The adjacent residues are also highly conserved. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. According to the Invitae report, 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Of the SNP variants listed in ClinVar as Pathogenic, all are missense. This variant was reported in 4 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 3 non-Finnish European individuals (MAF 0.003%) and 1 individual with “Other†ancestry. Overall MAF 0.002%. There is good sequencing coverage at this site. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 11, 2023 | The p.R187L variant (also known as c.560G>T), located in coding exon 1 of the DOLK gene, results from a G to T substitution at nucleotide position 560. The arginine at codon 187 is replaced by leucine, an amino acid with dissimilar 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at