Submissions for variant NM_182961.4(SYNE1):c.21706G>A (p.Ala7236Thr)

gnomAD frequency: 0.00006  dbSNP: rs202121741

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000401799	SCV000342222	uncertain significance	not provided	2016-05-22	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000662053	SCV000784389	uncertain significance	Autosomal recessive ataxia, Beauce type	2018-03-05	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001731565	SCV001984603	uncertain significance	not specified	2020-03-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002519299	SCV002980067	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2023-04-05	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: 288185). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. This variant is present in population databases (rs202121741, gnomAD 0.009%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 7165 of the SYNE1 protein (p.Ala7165Thr).
Revvity Omics, Revvity	RCV000401799	SCV003826340	uncertain significance	not provided	2020-02-18	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000401799	SCV001553956	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SYNE1 p.Ala7236Thr variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs202121741) and ClinVar (classified as uncertain significance by EGL Genetics and Genomic Research Center, Shahid Beheshti University of Medical Sciences). The variant was also identified in control databases in 15 of 282616 chromosomes at a frequency of 0.00005308 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 1 of 7214 chromosomes (freq: 0.000139), European (non-Finnish) in 12 of 128962 chromosomes (freq: 0.000093) and South Asian in 2 of 30616 chromosomes (freq: 0.000065), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Ala7236 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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.