Submissions for variant NM_182961.4(SYNE1):c.245G>A (p.Arg82Gln)

gnomAD frequency: 0.00006  dbSNP: rs143900928

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756742	SCV000884641	uncertain significance	not provided	2017-09-05	criteria provided, single submitter	clinical testing	The p.Arg82Gln variant (rs143900928) has not been reported in the medical literature. This variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.016% in the East Asian population (identified in 3 out of 18852 chromosomes; 0 homozygotes), and is listed in ClinVar with conflicting interpretations of pathogenicity (Variant ID: 285644). The arginine at codon 82 is weakly conserved considering 12 species (Alamut software v2.9.0), and computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: tolerated, PolyPhen2: benign, MutationTaster: disease causing). Based on the available information, the clinical significance of the p.Arg82Gln variant cannot be determined with certainty.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001339491	SCV001533241	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2023-08-02	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 618408). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. This variant is present in population databases (rs143900928, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 82 of the SYNE1 protein (p.Arg82Gln).
Genetic Services Laboratory, University of Chicago	RCV001815009	SCV002062009	uncertain significance	not specified	2021-09-23	criteria provided, single submitter	clinical testing	DNA sequence analysis of the SYNE1 gene demonstrated two sequence changes in this gene. The first sequence change, c.245G>A, in exon 5 that results in an amino acid change, p.Arg82Gln. This sequence change does not appear to have been previously described in individuals with SYNE1-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.015% in the East Asian subpopulation (dbSNP rs143900928). The p.Arg82Gln change affects a poorly conserved amino acid residue located in a domain of the SYNE1 protein that is known to be functional. The p.Arg82Gln substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Arg82Gln change remains unknown at this time.
Revvity Omics, Revvity	RCV000756742	SCV004237976	uncertain significance	not provided	2023-04-24	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000756742	SCV005621549	uncertain significance	not provided	2023-10-21	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Computational tools predict that this variant is not damaging.