NM_014908.4:c.1568T>C
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_014908.4(DOLK):c.1568T>C(p.Ile523Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,032 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. I523L) has been classified as Uncertain significance.
Frequency
Consequence
NM_014908.4 missense
Scores
Clinical Significance
Conservation
Publications
- DK1-congenital disorder of glycosylationInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DOLK | NM_014908.4 | c.1568T>C | p.Ile523Thr | missense_variant | Exon 1 of 1 | ENST00000372586.4 | NP_055723.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152144Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000278 AC: 7AN: 251490 AF XY: 0.0000221 show subpopulations
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727244 show subpopulations
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74328 show subpopulations
ClinVar
Submissions by phenotype
DK1-congenital disorder of glycosylation Uncertain:1
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 523 of the DOLK protein (p.Ile523Thr). This variant is present in population databases (rs774524497, gnomAD 0.007%). 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: 836909). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Cardiovascular phenotype Uncertain:1
The c.1568T>C (p.I523T) alteration is located in exon 1 (coding exon 1) of the DOLK gene. This alteration results from a T to C substitution at nucleotide position 1568, causing the isoleucine (I) at amino acid position 523 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at