Submissions for variant NM_022552.5(DNMT3A):c.2204A>G (p.Tyr735Cys)

dbSNP: rs147828672

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001776076	SCV002013768	likely pathogenic	not provided	2023-11-18	criteria provided, single submitter	clinical testing	Identified in a patient with Hodgkin lymphoma and a diagnosis of DNMT3A overgrowth syndrome, however, segregation, testing methodology, and additional clinical information were not provided (PMID: 34788385); Identified in at least one patient with autism; however, specific clinical information and presence of other possible variants was not provided (PMID: 31332282); Identified in multiple patients with acute myeloid leukemia, including as a somatic variant; however, specific clinical information was not provided (PMID: 21993668, 25964253, 31861499); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25964253, 31861499, 31785789, 31981491, 32581362, 25363760, 33238114, 34315901, 31974359, 35191116, 31988276, 32512379, 36353970, 32269971, 33832284, 36657266, 36013314, 34788385, 31332282, 21993668)
Mendelics	RCV002249617	SCV002516988	uncertain significance	not specified	2024-06-25	criteria provided, single submitter	clinical testing	This variant has been identified in an individual reported to have TBRS however without further clinical or segregation data (https://pubmed.ncbi.nlm.nih.gov/34788385/). It has also been reported as a de novo event in an individual from a cohort with autism spectrum disorder but without detailed clinical delineation (https://pubmed.ncbi.nlm.nih.gov/25363760/). In vitro studies demonstrate reduced methyltransferase activity and blocked mCA accumulation in mouse cortical neurons for this mutant (https://pubmed.ncbi.nlm.nih.gov/33238114/). This variant is present in heterozygosity in 29 out of 778790 alleles in population databases (gnomAD v4.0.1 non-UKB) which is higher than expected for an autosomal dominant neurodevelopmental disorder, although population data might be unreliable for this gene. Therefore, even though there is some evidence to suggest that this variant might be associated with neurodevelopmental phenotypes, it is still limited and for that reason we interpret it as a variant of uncertain significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471010	SCV002768181	pathogenic	Tatton-Brown-Rahman overgrowth syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with disease. Loss of function has been associated with Tatton-Brown-Rahman syndrome (MIM#615879) while gain of function has been associated with Heyn-Sproul-Jackson syndrome (MIM#618724) and demonstrated for two missense variants (PMID: 30478443). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 10 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3: 4 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated SAM-dependent MTase domain (Uniprot). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Tyr735Ser) has been reported in an individual with Tatton-Brown-Rahman syndrome (MIM#615879) (PMID: 29900417). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in at least two individuals described to have autism spectrum disorder and overgrowth syndrome with Hodgkin Lymphoma, one of which was proven to be a de novo event (PMID: 25363760, 34315901). (SP) 0906 - Segregation evidence for this variant is inconclusive. It was inherited from the mother, who is similarly affected. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro assays demonstrated a reduction in methylase activities, which was further supported by its ability to prevent build-up of methylated CA sites in embryonic mice neuronal cells (PMID: 33238114). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003798	SCV001162242	likely pathogenic	Myeloproliferative disorder		no assertion criteria provided	research
Department Of Pathology & Laboratory Medicine, University Of Pennsylvania	RCV003448984	SCV004176801	pathogenic	Malignant lymphoma, large B-cell, diffuse	2023-12-04	no assertion criteria provided	clinical testing	Pre-therapy specimen.
PreventionGenetics, part of Exact Sciences	RCV004746194	SCV005351178	likely pathogenic	DNMT3A-related disorder	2024-04-20	no assertion criteria provided	clinical testing	The DNMT3A c.2204A>G variant is predicted to result in the amino acid substitution p.Tyr735Cys. This variant has been reported in multiple individuals with Hodgkin lymphoma (Table 1, Ferris et al. 2022. PubMed ID: 34788385). This variant has also been reported in multiple individuals with autism spectrum disorder (Table S3, de novo, De Rubeis et al. 2014. PubMed ID: 25363760; Supplementary data 1, Zhou et al. 2022. PubMed ID: 35982159). An alternate nucleotide substitution affecting the same amino acid (p.Tyr735Ser) has been reported in multiple individuals with Tatton-Brown-Rahman syndrome and acute myeloid leukemia (Table 1, de novo, Tatton-Brown et al. 2018. PubMed ID: 29900417; Table 1, Ferris et al. 2022. PubMed ID: 34788385). This variant is reported in 0.0098% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and it has been classified as uncertain, likely pathogenic, and pathogenic by other institutions in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/812892/). Taken together, we interpret c.2204A>G (p.Tyr735Cys) as likely pathogenic.