Submissions for variant NM_182961.4(SYNE1):c.25751A>C (p.Asp8584Ala)

gnomAD frequency: 0.00041  dbSNP: rs41291047

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000710253	SCV000226191	uncertain significance	not provided	2018-07-10	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710253	SCV000615649	uncertain significance	not provided	2023-03-02	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). Computational tools disagree on the variant's effect on normal protein function.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000625938	SCV000746527	uncertain significance	Autosomal recessive ataxia, Beauce type	2017-12-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694728	SCV000823186	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 8536 of the SYNE1 protein (p.Asp8536Ala). This variant is present in population databases (rs41291047, gnomAD 0.09%), 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: 194451). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000710253	SCV001154906	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	SYNE1: BP1, BP4
Illumina Laboratory Services, Illumina	RCV001156685	SCV001318206	benign	Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000625938	SCV001318207	uncertain significance	Autosomal recessive ataxia, Beauce type	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000710253	SCV001794579	uncertain significance	not provided	2024-12-04	criteria provided, single submitter	clinical testing	Reported previously with a variant on the opposite allele (in trans) in a patient with Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) in published literature; however, the patient also was compound heterozygous for two variants in another gene that may have been responsible for the phenotype (PMID: 26302956); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26302956)
Ambry Genetics	RCV004020072	SCV004960358	uncertain significance	Inborn genetic diseases	2021-08-13	criteria provided, single submitter	clinical testing	The c.25607A>C (p.D8536A) alteration is located in exon 142 (coding exon 141) of the SYNE1 gene. This alteration results from an A to C substitution at nucleotide position 25607, causing the aspartic acid (D) at amino acid position 8536 to be replaced by an alanine (A). Based on data from gnomAD, the C allele has an overall frequency of 0.05% (152/282854) total alleles studied. The highest observed frequency was 0.09% (117/129158) of European (non-Finnish) alleles. This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767119	SCV005381728	uncertain significance	not specified	2024-08-27	criteria provided, single submitter	clinical testing	Variant summary: SYNE1 c.25607A>C (p.Asp8536Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 251444 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SYNE1 causing SYNE1-Related Disorders, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.25607A>C 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: 194451). Based on the evidence outlined above, the variant was classified as uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000710253	SCV001744415	uncertain significance	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV004545754	SCV001749511	not provided	SYNE1-related disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 03-06-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000710253	SCV001954624	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000710253	SCV001964273	uncertain significance	not provided		no assertion criteria provided	clinical testing