Submissions for variant NM_001130823.3(DNMT1):c.575C>T (p.Ala192Val)

gnomAD frequency: 0.00023  dbSNP: rs62621089

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000757174	SCV000293761	likely benign	not provided	2023-03-17	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Illumina Laboratory Services, Illumina	RCV001086953	SCV000410259	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757174	SCV000885309	uncertain significance	not provided	2018-05-07	criteria provided, single submitter	clinical testing	The DNMT1 c.575C>T; p.Ala192Val variant (rs62621089, ClinVar variant ID 246280), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with a South Asian population frequency of 0.2% (identified on 67 out of 30,782 chromosomes). The alanine at position 192 is weakly conserved, considering 12 species, and computational analyses of the effects of the p.Ala192Val variant on protein structure and function make conflicting predictions (SIFT: damaging, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Ala192Val variant cannot be determined with certainty.
Invitae	RCV001086953	SCV001020732	likely benign	Hereditary sensory neuropathy-deafness-dementia syndrome	2024-01-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002347928	SCV002644224	likely benign	Inborn genetic diseases	2020-02-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
CeGaT Center for Human Genetics Tuebingen	RCV000757174	SCV004139493	benign	not provided	2022-04-01	criteria provided, single submitter	clinical testing	DNMT1: BS1, BS2