Submissions for variant NM_182961.4(SYNE1):c.14263C>T (p.Leu4755Phe)

gnomAD frequency: 0.00100  dbSNP: rs41301343

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000180075	SCV000232440	likely benign	not specified	2017-04-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000714610	SCV000461171	uncertain significance	Autosomal recessive ataxia, Beauce type	2018-01-12	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	RCV000316351	SCV000461172	benign	Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2018-01-12	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.
Athena Diagnostics Inc	RCV000180075	SCV000615560	benign	not specified	2020-06-02	criteria provided, single submitter	clinical testing
Invitae	RCV000533703	SCV000649042	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 4684 of the SYNE1 protein (p.Leu4684Phe). This variant is present in population databases (rs41301343, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of ataxia (PMID: 31692161). ClinVar contains an entry for this variant (Variation ID: 198671). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000714610	SCV000845320	uncertain significance	Autosomal recessive ataxia, Beauce type	2018-08-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000710240	SCV001154933	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	SYNE1: BP4, BS2
GeneDx	RCV000710240	SCV001766173	likely benign	not provided	2020-10-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24892279, 31692161)
Genetic Services Laboratory, University of Chicago	RCV000180075	SCV002069808	uncertain significance	not specified	2018-07-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000710240	SCV002542250	uncertain significance	not provided	2022-01-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003927696	SCV004740749	likely benign	SYNE1-related condition	2023-05-05	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).