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

gnomAD frequency: 0.00032  dbSNP: rs141586001

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000710251	SCV000225975	uncertain significance	not provided	2017-08-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000710251	SCV000527443	likely benign	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000174643	SCV000615643	likely benign	not specified	2021-04-23	criteria provided, single submitter	clinical testing
Invitae	RCV000647654	SCV000769452	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 8170 of the SYNE1 protein (p.His8170Gln). This variant is present in population databases (rs141586001, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 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, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Ambry Genetics	RCV002516638	SCV003636534	likely benign	Inborn genetic diseases	2021-10-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003390897	SCV004111669	uncertain significance	SYNE1-related condition	2023-02-14	criteria provided, single submitter	clinical testing	The SYNE1 c.24510C>G variant is predicted to result in the amino acid substitution p.His8170Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including one homozygous individual (http://gnomad.broadinstitute.org/variant/6-152469433-G-C). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252114	SCV001427863	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing