Submissions for variant NM_006950.3(SYN1):c.1648G>A (p.Ala550Thr)

dbSNP: rs397514680

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000034816	SCV001554659	uncertain significance	Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders	2023-09-26	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects SYN1 function (PMID: 21441247, 26173895). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 41889). This variant is also known as p.Ala548Thr. This missense change has been observed in individuals with SYN1-related conditions (PMID: 21441247; Invitae). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 550 of the SYN1 protein (p.Ala550Thr).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330407	SCV004039560	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing	Variant summary: SYN1 c.1648G>A (p.Ala550Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 17090 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1648G>A has been reported in the literature in individuals affected with epilepsy, autism spectrum disorder, and schizophrenia (examples: Fassio_2011, and Mojarad_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders. Experimental studies have reported the variant affects normal protein function however is insufficient to determine the role of this variant in disease (examples: Fassio_2011, and Tang_2014). The following publications have been ascertained in the context of this evaluation (PMID: 21441247, 33526774, 26173895). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003952400	SCV004773657	uncertain significance	SYN1-related condition	2024-02-08	criteria provided, single submitter	clinical testing	The SYN1 c.1648G>A variant is predicted to result in the amino acid substitution p.Ala550Thr. This variant has been reported to be causative for autism spectrum disorders with or without epilepsy in four unrelated French Canadian patients (Fassio et al. 2011 et al. PubMed ID: 21441247). Functional studies showed that this variant displayed impaired targeting to nerve terminals (Fassio et al. 2011 et al. PubMed ID: 21441247; Tang et al. 2015. PubMed ID: 26173895, reported as A548T). This variant has not been reported in a large population database, indicating this variant is rare. However, it has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/41889/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
OMIM	RCV000034816	SCV000058378	pathogenic	Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders	2011-06-15	no assertion criteria provided	literature only