ClinVar Genomic variation as it relates to human health

The SYNE1 c.25237G>A; p.Glu8413Lys variant (rs119103248), also reported as c.2132G>A; p.Glu646Lys for a shorter alternate transcript by Zhang et al. (2007), was identified in an individual with Emery-Dreifuss Muscular Dystrophy-like symptoms; however, it has not been demonstrated to be disease-causing (Zhang 2007). This variant is reported in ClinVar (Variation ID: 2334) and is found in the Latino population with an overall allele frequency of 0.16% (55/34420 alleles) in the Genome Aggregation Database. The glutamate at codon 8413 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Glu8413Lys variant is uncertain at this time. References: Zhang Q et al. Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity. Hum Mol Genet. 2007 Dec 1;16(23):2816-33.

This variant is associated with the following publications: (PMID: 17761684)

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Variant summary: SYNE1 c.25237G>A (p.Glu8413Lys) results in a conservative amino acid change located in a spectrin repeat (IPR002017) of 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 0.00067 in 251482 control chromosomes, predominantly at a frequency of 0.0017 within the Latino subpopulation in the gnomAD database. This relatively high frequency suggests that the variant is likely not associated with a high penetrance, early onset dominant disease phenotype. The variant c.25237G>A has been reported in the literature in individuals affected with phenotypes suggestive of muscular disease (e.g. Zhang_2007, Kuhn_2016, Cerino_2021, Nallamilli_2018), however without strong evidence of causality (i.e. lack cosegregation evidence, atypical phenotype, or presence of other variants was noted in some of these cases). At least one of these publications reports experimental evidence evaluating an impact on protein function, however these results showed no damaging effect of this variant (Zhang_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17761684, 32934002, 32934002, 30564623). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign.

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 8413 of the SYNE1 protein (p.Glu8413Lys). This variant is present in population databases (rs119103248, 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 Emery–Dreifuss muscular dystrophy (PMID: 17761684). ClinVar contains an entry for this variant (Variation ID: 2334). 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. Experimental studies have shown that this missense change does not substantially affect SYNE1 function (PMID: 17761684). 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.

SYNE1: BP4