Submissions for variant NM_182961.4(SYNE1):c.15337G>A (p.Val5113Ile)

gnomAD frequency: 0.00054  dbSNP: rs139170018

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000710243	SCV000232453	uncertain significance	not provided	2017-06-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000195238	SCV000249082	uncertain significance	not specified	2014-06-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000325682	SCV000461149	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 Laboratory Services, Illumina	RCV000382649	SCV000461150	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	RCV000710243	SCV000615567	likely benign	not provided	2020-03-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542729	SCV000649048	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 5042 of the SYNE1 protein (p.Val5042Ile). This variant is present in population databases (rs139170018, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and sudden infant death syndrome (PMID: 28074886, 28750076). ClinVar contains an entry for this variant (Variation ID: 198681). 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: "Benign"; Align-GVGD: "Class C25"). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000710243	SCV001154932	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	SYNE1: BP4
GeneDx	RCV000710243	SCV001777399	uncertain significance	not provided	2025-01-22	criteria provided, single submitter	clinical testing	Reported previously in the heterozygous state in a patient with hypertrophic cardiomyopathy; however, additional information was not provided (PMID: 28750076); Reported previously in the heterozygous state in an individual tested as part of a sudden infant death syndrome cohort; however, additional clinical information was not provided (PMID: 28074886); Reported previously in an individual with cerebellar syndrome and CPEO who also harbored a second variant in SYNE1 (phase unknown) (PMID: 29625556); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28750076, 28074886, 29625556)
Centogene AG - the Rare Disease Company	RCV000382649	SCV002028330	uncertain significance	Autosomal recessive ataxia, Beauce type	2019-07-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734802	SCV005359820	uncertain significance	SYNE1-related disorder	2024-05-22	no assertion criteria provided	clinical testing	The SYNE1 c.15124G>A variant is predicted to result in the amino acid substitution p.Val5042Ile. This variant has been observed in an infant with sudden infant death syndrome as a variant of uncertain significance and in a patient with hypertrophic cardiomyopathy (Supp. Table 4 in Neubauer et al. 2017. PubMed ID: 28074886; Reported as c.15337G>A, p.Val5113Ile with NM_182961.3 Supp. Table 5 in Forleo et al. 2017. PubMed ID: 28750076). This variant has also been reported in the compound heterozygous state in a patient with a cerebellar syndrome (reported as c.15337G>A, p.Val5113Ile with NM_182961.3 in Plutino et al. 2018. PubMed ID: 29625556). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.