ClinVar Miner

Submissions for variant NM_182961.4(SYNE1):c.24723C>G (p.His8241Gln) (rs141586001)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000710251 SCV000225975 uncertain significance not provided 2017-08-07 criteria provided, single submitter clinical testing
GeneDx RCV000174643 SCV000527443 likely benign not specified 2016-12-29 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.
Athena Diagnostics Inc RCV000710251 SCV000615643 uncertain significance not provided 2019-08-07 criteria provided, single submitter clinical testing
Invitae RCV000647654 SCV000769452 uncertain significance Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 8170 of the SYNE1 protein (p.His8170Gln). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and glutamine. This variant is present in population databases (rs141586001, ExAC 0.1%). This variant has not been reported in the literature in individuals with SYNE1-related disease. ClinVar contains an entry for this variant (Variation ID: 194306). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000710251 SCV000884634 uncertain significance not provided 2017-05-31 criteria provided, single submitter clinical testing The p.His8170Gln variant (rs141586001) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a population frequency of 0.1 percent in the European Non-Finnish population (identified on 145 out of 125,962 chromosomes), and has been reported to the ClinVar database with conflicting interpretations. The histidine at position 8170 is weakly conserved and computational analyses of the p.His8170Gln variant on protein structure and function indicate a neutral effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.His8170Gln variant with certainty.

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