Submissions for variant NM_182961.4(SYNE1):c.8546T>C (p.Val2849Ala)

gnomAD frequency: 0.00029  dbSNP: rs375079396

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000277505	SCV000337966	uncertain significance	not provided	2015-12-28	criteria provided, single submitter	clinical testing
Invitae	RCV000647637	SCV000769435	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2856 of the SYNE1 protein (p.Val2856Ala). This variant is present in population databases (rs375079396, 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: 285095). 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: "Benign"; Align-GVGD: "Class C55"). 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.
GeneDx	RCV000277505	SCV001772137	uncertain significance	not provided	2021-03-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Revvity Omics, Revvity	RCV000277505	SCV003824703	uncertain significance	not provided	2019-08-07	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000277505	SCV001549624	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SYNE1 p.Val2849Ala variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs375079396), ClinVar (classified as a VUS by EGL Genetics and Invitae) and LOVD 3.0 (classified as a VUS). The variant was also identified in control databases in 25 of 282710 chromosomes at a frequency of 0.000088 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 19 of 24968 chromosomes (freq: 0.000761) and Latino in 6 of 35434 chromosomes (freq: 0.000169), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other or South Asian populations. The p.Val2849 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.