Submissions for variant NM_182961.4(SYNE1):c.23315G>A (p.Arg7772Gln)

gnomAD frequency: 0.00432  dbSNP: rs138787771

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000174436	SCV000225737	likely benign	not specified	2015-01-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000283826	SCV000460945	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	RCV000341118	SCV000460946	likely benign	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 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.
GeneDx	RCV000513503	SCV000514842	benign	not provided	2020-05-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31692161, 32075053)
CeGaT Center for Human Genetics Tuebingen	RCV000513503	SCV000609235	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	SYNE1: BP4, BS2
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513503	SCV000610336	likely benign	not provided	2017-03-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083895	SCV000649132	likely benign	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2024-01-19	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000513503	SCV000844266	benign	not provided	2018-10-12	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000513503	SCV005227857	likely benign	not provided		criteria provided, single submitter	not provided
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000174436	SCV000280488	uncertain significance	not specified	2014-04-24	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg7701Gln (aka R7701Q, c.23102 G>A) in SYNE1 (using NM_033071.3). The variant is novel. It is a non-conservative amino acid change with a positively charged arginine being changed to a neutral, polar glutamine. The arginine at codon 7701 is not conserved across species. In silico analysis predicts a benign effect on protein structure and function (per lab report). SYNE1 encodes nesprin 1 (nuclear envelope spectrin repeat 1). Nesprin 1 and 2 are associated with the nuclear membrane and bind lamin A and emerin. These genes are highly expressed in both heart and skeletal muscle. It has been suggested that variants in SYNE1 may contribute to Emery-Dreiffus muscular dystrophy (EDMD). Using a candidate gene approach, Zang et al (2011), sequenced SYNE1 and SYNE2 (encoding nesprin 2) in 190 patients with EDMD and EDMD-like phenotypes who did not have causative variants in LMNA or EMD. This identified three patients who carried an SYNE1 missense variant that was not present in 192 control individuals. One of these patients was a compound heterozygote for a missense variant in SYNE2. Only minimal segregation analysis could be performed. The patient who was a compound heterozygote had an affected mother, who carried the SYNE2 variant and a seemingly unaffected father, who carried the SYNE1 variant. Dr. Beth McNally’s group reported on a patient with dilated cardiomyopathy requiring heart transplant who had a missense variant in SYNE1 (p.Arg374His) (Puckelwartz et al 2010). They found that mice lacking the carboxy-terminus of nesprin-1develop cardiomyopathy with conduction system disease. SYNE1 has also been linked to autosomal recessive spinocerebellar ataxia 8. Nesprin-1 is over 8700 amino acids long. p.Arg7701Gln was observed in 47 of 8600 alleles from European Americans in the NHLBI ESP, which presumably indicated 47 of 4300 individuals were heterozygous for the variant. 12 of 4406 African American alleles (likely 6 of 2203 individuals) (as of April 23rd, 2013).
PreventionGenetics, part of Exact Sciences	RCV004537367	SCV004728838	likely benign	SYNE1-related disorder	2019-05-03	no assertion criteria provided	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).