19-10155018-A-G
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_001130823.3(DNMT1):c.1531T>C(p.Tyr511His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y511C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001130823.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNMT1 | NM_001130823.3 | c.1531T>C | p.Tyr511His | missense_variant | 20/41 | ENST00000359526.9 | |
DNMT1 | NM_001318730.2 | c.1483T>C | p.Tyr495His | missense_variant | 19/40 | ||
DNMT1 | NM_001379.4 | c.1483T>C | p.Tyr495His | missense_variant | 19/40 | ||
DNMT1 | NM_001318731.2 | c.1168T>C | p.Tyr390His | missense_variant | 20/41 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNMT1 | ENST00000359526.9 | c.1531T>C | p.Tyr511His | missense_variant | 20/41 | 1 | NM_001130823.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 36
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary sensory neuropathy-deafness-dementia syndrome Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 26, 2013 | - - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2018 | The Y511H pathogenic variant in the DNMT1 gene has been reported previously using alternate nomenclature (Y495H) in association with autosomal dominant hereditary sensory and autonomic neuropathy type 1E (HSAN1E). The Y511H variant was reported in two brothers with hearing loss, peripheral sensory neuropathy with lesions leading toe amputations, tremor, cognitive and memory decline, psychiatric manifestations and seizures with similar symptoms reported in one son and in their father, paternal grandmother and paternal great grandmother (Klein et al., 2013). Baets et al. (2015), reported a kindred of 10 individuals across two generations with peripheral sensory neuropathy, foot ulcers, severe hearing loss, cognitive decline, psychiatric complaints, lymphoedema and cerebellar atrophy with molecular confirmation of the Y511H variant in the only two individuals available for testing. The Y511H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y511H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies have shown the Y511H variant protein is mislocalized from the nucleus to the cytosol during the G2 phase, forming cytosolic aggegates that lead to early degradation and toxic cell stress (Baets et al., 2015). The Y511H variant is located in the TS domain, as are all other pathogenic variants in the DMNT1 gene, and the Y511 residue is a hotspot for mutation within the region, as another substitution at the same residue (Y511C) has been reported in the Human Gene Mutation Database in association with DMNT1-related disorders (Stenson et al., 2014). Therefore, we interpret Y511H as a pathogenic variant - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at