Submissions for variant NM_182961.4(SYNE1):c.11675T>C (p.Leu3892Ser)

gnomAD frequency: 0.00012  dbSNP: rs180727534

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000713587	SCV000334006	uncertain significance	not provided	2015-08-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000393083	SCV000461259	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.
Illumina Laboratory Services, Illumina	RCV000284405	SCV000461260	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.
Athena Diagnostics	RCV000713587	SCV000844212	uncertain significance	not provided	2022-10-19	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The available data on the frequency of this variant in large general population databases was not informative towards the evaluation of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000815827	SCV000956299	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3877 of the SYNE1 protein (p.Leu3877Ser). This variant is present in population databases (rs180727534, gnomAD 0.08%). This missense change has been observed in individual(s) with intellectual disability, spastic paraplegia, axon neuropathy and leukoencephalopathy (PMID: 24123876). This variant is also known as p.Leu3892Ser. ClinVar contains an entry for this variant (Variation ID: 92125). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
GeneDx	RCV000713587	SCV002568568	uncertain significance	not provided	2022-08-17	criteria provided, single submitter	clinical testing	The p.(L3877S) variant in the SYNE1gene has been previously reported as p.(L3892S) due to alternate nomenclature along with two other missense variants, one in cis and one in trans, in two siblings with mild intellectual disability, spastic paraplegia, axon neuropathy, and leukencephalopathy (Schuurs-Hoeijmakers et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24123876)
Revvity Omics, Revvity	RCV000713587	SCV003825304	uncertain significance	not provided	2023-04-20	criteria provided, single submitter	clinical testing
OMIM	RCV000077791	SCV000109617	uncertain significance	Intellectual disability	2013-12-01	no assertion criteria provided	literature only