ClinVar Miner

Submissions for variant NM_182961.4(SYNE1):c.23315G>A (p.Arg7772Gln) (rs138787771)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000174436 SCV000225737 likely benign not specified 2015-01-12 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000283826 SCV000460945 likely benign Emery-Dreifuss muscular dystrophy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000341118 SCV000460946 likely benign Cerebellar ataxia 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000174436 SCV000514842 likely benign not specified 2017-12-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513503 SCV000609235 uncertain significance not provided 2017-06-30 criteria provided, single submitter clinical testing
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
Invitae RCV000513503 SCV000649132 likely benign not provided 2019-03-01 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000513503 SCV000844266 likely benign not provided 2017-09-26 criteria provided, single submitter clinical testing
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).

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