Submissions for variant NM_001080421.3(UNC13A):c.2441C>T (p.Pro814Leu)

dbSNP: rs2076985517

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV003128383	SCV003804674	likely pathogenic	Cerebellar ataxia; Febrile seizure (within the age range of 3 months to 6 years); Delayed speech and language development; Tremor; Developmental regression	2023-01-02	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_SUP, PS3_SUP, PS4_MOD, PM2_SUP, PP2
Institute of Human Genetics, University of Leipzig Medical Center	RCV003326146	SCV004032253	likely pathogenic	UNC13A-associated disorder	2023-01-02	criteria provided, single submitter	clinical testing	Criteria applied: PS4_MOD, PS2_MOD, PS3_SUP, PM2_SUP, PP2
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004789517	SCV005400309	likely pathogenic	Neurodevelopmental disorder	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, gain-of-function has been demonstrated for the single variant reported thus far (PMID: 28192369). (I) 0107 - This gene is associated with autosomal dominant disease (PMID: 28192369; unpublished data, personal communications). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as de novo in two individuals with developmental delay, movement disorders and seizures (PMID: 28192369, ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Both in vitro assays and animal modelling demonstrated a gain-of-function based on increase in postsynaptic currents and hypersecretion of acetylcholine (PMID: 28192369). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV001290299	SCV001478330	uncertain significance	not provided	2021-01-29	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001290299	SCV001809095	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001290299	SCV001929761	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001290299	SCV002036653	likely pathogenic	not provided		no assertion criteria provided	clinical testing