Submissions for variant NM_022552.5(DNMT3A):c.1903C>T (p.Arg635Trp)

gnomAD frequency: 0.00006  dbSNP: rs144689354

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000433567	SCV000337716	likely pathogenic	not provided	2016-03-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000433567	SCV000521279	pathogenic	not provided	2021-08-30	criteria provided, single submitter	clinical testing	Previously reported in two unrelated individuals who underwent whole genome sequencing to identify candidate genes in cohorts of patients with autism spectrum disorders; however limited clinical information is available on the probands, and in one proband a second de novo variant in another gene was also identified (Jiang et al., 2013; Yuen et al., 2016); Published functional studies suggest this variant significantly disrupts catalytic activity of DNMT3a (Khrabrova et al., 2019); This variant is associated with the following publications: (PMID: 22077061, 23370706, 26874914, 32269971, 31332282, 21904384, 23507483, 27525107, 28263302, 31981491, 32355762, 33219223, 23849776, 31861499)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000367312	SCV000815919	uncertain significance	Tatton-Brown-Rahman overgrowth syndrome	2024-05-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 635 of the DNMT3A protein (p.Arg635Trp). This variant is present in population databases (rs144689354, gnomAD 0.01%). This missense change has been observed in individual(s) with autism spectrum disorder (PMID: 23849776, 27525107, 31981491). ClinVar contains an entry for this variant (Variation ID: 284904). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNMT3A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DNMT3A function (PMID: 31861499). This variant disrupts the p.Arg635 amino acid residue in DNMT3A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32435502; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Molecular Genetics Lab, CHRU Brest	RCV003883148	SCV004697760	likely pathogenic	Acute myeloid leukemia; Tatton-Brown-Rahman overgrowth syndrome; Heyn-Sproul-Jackson syndrome		criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, CHRU Nancy	RCV000367312	SCV004805241	likely pathogenic	Tatton-Brown-Rahman overgrowth syndrome	2024-03-24	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000433567	SCV005197762	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
GenomeConnect - Brain Gene Registry	RCV003313065	SCV004012824	not provided	Autism spectrum disorder; Tatton-Brown-Rahman overgrowth syndrome		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 09-13-2021 by Lab GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
PreventionGenetics, part of Exact Sciences	RCV004745319	SCV005361059	uncertain significance	DNMT3A-related disorder	2024-06-07	no assertion criteria provided	clinical testing	The DNMT3A c.1903C>T variant is predicted to result in the amino acid substitution p.Arg635Trp. This variant has been reported as a de novo variant in two individuals with autism, but one individual also harbored another de novo variant in another gene, MICALCL (Jiang et al. 2013. PubMed ID: 23849776; Yuen et al. 2017. PubMed ID: 28263302, table S3 genomic position 25466800). In ClinVar, the DNMT3A variant is reported as uncertain and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/284904/). This variant is reported in 0.023% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.