Submissions for variant NM_182961.4(SYNE1):c.10396C>G (p.Leu3466Val) (rs150637898)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000710234	SCV000339161	uncertain significance	not provided	2016-02-12	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000306417	SCV000461303	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina	RCV000347469	SCV000461304	uncertain significance	Spinocerebellar ataxia, autosomal recessive 8	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.
GeneDx	RCV000710234	SCV000491802	uncertain significance	not provided	2016-11-22	criteria provided, single submitter	clinical testing	The L3473V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was observed on 16/10404 (0.15%) alleles from individuals of African background in the Exome Aggregation Consortium (ExAC) data set. The L3473V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Athena Diagnostics Inc	RCV000710234	SCV000615527	likely benign	not provided	2018-10-30	criteria provided, single submitter	clinical testing
Invitae	RCV001242547	SCV001415642	uncertain significance	Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2019-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with valine at codon 3473 of the SYNE1 protein (p.Leu3473Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs150637898, ExAC 0.2%). This variant has not been reported in the literature in individuals with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 285937). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.