Submissions for variant NM_203446.3(SYNJ1):c.1744A>G (p.Thr582Ala)

gnomAD frequency: 0.00004  dbSNP: rs370817503

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001996697	SCV002227163	uncertain significance	Early-onset Parkinson disease 20; Developmental and epileptic encephalopathy, 53	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 621 of the SYNJ1 protein (p.Thr621Ala). This variant is present in population databases (rs370817503, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SYNJ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1447060). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SYNJ1 protein function. 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.
Ambry Genetics	RCV002563484	SCV003583708	uncertain significance	Inborn genetic diseases	2021-09-15	criteria provided, single submitter	clinical testing	The c.1861A>G (p.T621A) alteration is located in exon 15 (coding exon 15) of the SYNJ1 gene. This alteration results from a A to G substitution at nucleotide position 1861, causing the threonine (T) at amino acid position 621 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003120770	SCV003800949	uncertain significance	not specified	2023-01-12	criteria provided, single submitter	clinical testing	Variant summary: SYNJ1 c.1861A>G (p.Thr621Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250274 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1861A>G in individuals affected with SYNJ1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.