Submissions for variant NM_182961.4(SYNE1):c.21782G>A (p.Arg7261Gln)

gnomAD frequency: 0.00030  dbSNP: rs61742716

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726696	SCV000590327	uncertain significance	not provided	2024-05-08	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Athena Diagnostics	RCV000726696	SCV000615614	uncertain significance	not provided	2024-05-17	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 higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) Polyphen and MutationTaster predict this amino acid change may be benign.
Eurofins Ntd Llc (ga)	RCV000726696	SCV000702180	uncertain significance	not provided	2016-10-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801869	SCV000941667	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2025-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 7190 of the SYNE1 protein (p.Arg7190Gln). This variant is present in population databases (rs61742716, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 432582). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV002524087	SCV003721232	uncertain significance	Inborn genetic diseases	2021-09-27	criteria provided, single submitter	clinical testing	The c.21569G>A (p.R7190Q) alteration is located in exon 118 (coding exon 117) of the SYNE1 gene. This alteration results from a G to A substitution at nucleotide position 21569, causing the arginine (R) at amino acid position 7190 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000726696	SCV003824055	uncertain significance	not provided	2021-06-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987567	SCV004804292	uncertain significance	not specified	2024-01-08	criteria provided, single submitter	clinical testing	Variant summary: SYNE1 c.21569G>A (p.Arg7190Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251332 control chromosomes. To our knowledge, no occurrence of c.21569G>A in individuals affected with SYNE1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 432582). Based on the evidence outlined above, the variant was classified as uncertain significance.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783796	SCV005397485	uncertain significance	Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2023-07-28	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) at position 21569 of the coding sequence of the SYNE1 gene that results in an arginine to glutamine amino acid change at residue 7190 of the SYNE1 protein. This variant falls in spectrin repeat 62 of the SYNE1 protein. This is a previously reported variant (ClinVar 432582) that has not been observed in the literature in individuals with SYNE1-related disease, to our knowledge. This variant is present in 31 of 282738 alleles (0.0110%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this arginine to glutamine amino acid change would be neutral, and the Arg7190 residue at this position is poorly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: BP1, BP4, PM2