Submissions for variant NM_004380.3(CREBBP):c.4837G>A (p.Val1613Met)

gnomAD frequency: 0.00004  dbSNP: rs766085073

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001658799	SCV001873911	uncertain significance	not provided	2021-08-11	criteria provided, single submitter	clinical testing	Identified in a patient with features of Rubinstein-Taybi syndrome who also harbored other multiple novel CREBBP variants (Sharma 2010); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20689175, 12070251)
Mendelics	RCV002246449	SCV002518156	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002539614	SCV003498314	likely benign	Rubinstein-Taybi syndrome	2024-10-30	criteria provided, single submitter	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV003319995	SCV004023412	likely pathogenic	Tip-toe gait	2021-03-25	no assertion criteria provided	clinical testing	Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.
PreventionGenetics, part of Exact Sciences	RCV004743561	SCV005367613	uncertain significance	CREBBP-related disorder	2024-05-14	no assertion criteria provided	clinical testing	The CREBBP c.4837G>A variant is predicted to result in the amino acid substitution p.Val1613Met. This variant has been reported as g.5262C>T in an individual with Rubinstein-Taybi syndrome who also had several other missense and intronic variants in CREBBP (Sample ID: RSTS13a, Supplementary Table 4, Sharma et al. 2010. PubMed ID: 20689175). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.