ClinVar Miner

Submissions for variant NM_020549.4(CHAT):c.1061C>T (p.Thr354Met) (rs769234940)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626952 SCV000747655 pathogenic Apnea, central sleep; Respiratory insufficiency; Febrile seizures; Pes planus; Lactic acidosis; External ophthalmoplegia; Gastroesophageal reflux; Decreased activity of the pyruvate dehydrogenase complex; Progressive muscle weakness; Progressive ptosis; Aspiration pneumonia 2017-01-01 criteria provided, single submitter clinical testing
Invitae RCV000636628 SCV000758067 uncertain significance Familial infantile myasthenia 2020-08-23 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 354 of the CHAT protein (p.Thr354Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs769234940, ExAC 0.001%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with congenital myasthenic syndrome with episodic apnea (PMID: 15701560). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease.. ClinVar contains an entry for this variant (Variation ID: 523528). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). 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. 5

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