ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.382C>A (p.Pro128Thr)

gnomAD frequency: 0.00013  dbSNP: rs146601335
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235285 SCV000294177 uncertain significance not specified 2017-04-04 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DNMT1 gene. The P128T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P128T variant is observed in 18/66,718 (0.03%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P128T 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. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000706094 SCV000835126 uncertain significance Hereditary sensory neuropathy-deafness-dementia syndrome 2024-01-02 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 128 of the DNMT1 protein (p.Pro128Thr). This variant is present in population databases (rs146601335, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DNMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 246583). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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.
Illumina Laboratory Services, Illumina RCV000706094 SCV001284509 benign Hereditary sensory neuropathy-deafness-dementia syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Ambry Genetics RCV002356327 SCV002623239 likely benign Inborn genetic diseases 2019-11-18 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000706094 SCV002769307 likely benign Hereditary sensory neuropathy-deafness-dementia syndrome 2020-05-01 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely benign. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from proline to threonine (exon 4). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (48 heterozygotes, 0 homozygotes). (P) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (highest allele frequency: 9 heterozygotes, 0 homozygotes). (N) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0504 - Same amino acid change has been observed in mammals. (B) 0600 - Variant is located in an annotated domain or motif (MIP-T3 superfamily; NCBI). (N) 0708 - Comparable variant (p.Pro128Ser) has been reported as a VUS (ClinVar). (N) 0806 – This variant has been reported as both likely benign (LOVD) and as a VUS (ClinVar). (N) 0905 - No segregation evidence has been identified for this variant in the literature. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

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