Submissions for variant NM_182961.4(SYNE1):c.13421G>A (p.Arg4474Gln)

gnomAD frequency: 0.00009  dbSNP: rs771898973

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000297082	SCV000461203	uncertain significance	Autosomal recessive ataxia, Beauce type	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000354118	SCV000461204	likely benign	Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV000522411	SCV000620955	uncertain significance	not provided	2023-07-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32579932)
Athena Diagnostics Inc	RCV000522411	SCV001145876	likely benign	not provided	2019-04-12	criteria provided, single submitter	clinical testing
Invitae	RCV002523559	SCV003033101	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2022-07-11	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. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 355876). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. This variant is present in population databases (rs771898973, gnomAD 0.1%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4403 of the SYNE1 protein (p.Arg4403Gln).
Ambry Genetics	RCV002524470	SCV003753464	uncertain significance	Inborn genetic diseases	2021-08-16	criteria provided, single submitter	clinical testing	The c.13208G>A (p.R4403Q) alteration is located in exon 77 (coding exon 76) of the SYNE1 gene. This alteration results from a G to A substitution at nucleotide position 13208, causing the arginine (R) at amino acid position 4403 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000522411	SCV003822781	uncertain significance	not provided	2019-11-18	criteria provided, single submitter	clinical testing