ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.1373C>T (p.Thr458Ile) (rs61729954)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000676372 SCV000333837 uncertain significance not provided 2015-08-13 criteria provided, single submitter clinical testing
Invitae RCV001082461 SCV000562824 likely benign Spastic paraplegia 2020-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000335849 SCV000565514 uncertain significance not specified 2016-10-18 criteria provided, single submitter clinical testing The T458I variant in the SACS gene was initially reported in two unrelated individuals with anatypical presentation of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS).However, as this variant was also observed with a frequency of 0.40% (14/3500) in controlchromosomes, the authors interpreted T458I as a variant of unknown significance (Synofzik et al.,2013). The T458I variant has also been reported in the compound heterozygous state in an individualwith ARSCAS who harbored a 1.5 Mb deletion which encompassed the entire opposite SACS allele(Romano et al., 2013). In addition, the T458I variant has been observed along with another SACSmissense variant in two individuals with progressive myoclonus epilepsy (Muona et al., 2015;Nascimento et al., 2016). Although not present in the homozygous state, the NHLBI ESP ExomeSequencing Project reports T458I was observed in 29/8600 (0.34%) alleles from individuals ofEuropean American background. The T458I variant is a non-conservative amino acid substitution,which occurs at a position that is conserved across species. In silico analysis predicts this variant isprobably damaging to the protein structure/function. Given the available data, we interpret T458I as avariant of uncertain significance.
Unit for Genetic & Epidemiological Research on Neurological Disorders,Instituto de Investigação e Inovação em Saúde RCV000516147 SCV000574488 uncertain significance Hereditary spastic paraplegia 2017-03-07 criteria provided, single submitter research
Athena Diagnostics Inc RCV000676372 SCV000614939 benign not provided 2019-02-06 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000603816 SCV000744372 uncertain significance Charlevoix-Saguenay spastic ataxia 2015-09-21 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000676372 SCV001148952 uncertain significance not provided 2019-07-01 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000603816 SCV001737270 likely benign Charlevoix-Saguenay spastic ataxia 2021-05-18 criteria provided, single submitter clinical testing
Genomics England Pilot Project,Genomics England RCV000603816 SCV001760321 likely pathogenic Charlevoix-Saguenay spastic ataxia criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000603816 SCV000733512 uncertain significance Charlevoix-Saguenay spastic ataxia no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000676372 SCV000802148 uncertain significance not provided 2016-02-19 no assertion criteria provided clinical testing
Natera, Inc. RCV000603816 SCV001464188 likely benign Charlevoix-Saguenay spastic ataxia 2020-06-18 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000603816 SCV001552907 uncertain significance Charlevoix-Saguenay spastic ataxia no assertion criteria provided clinical testing The p.Thr458Ile was identified in the proband in trans with the SACS p.Leu266Ile variant of uncertain significance. The p.Thr458Ile variant was previously identified in two patients with Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS), and classified as a VUS (Synofzik_2013_PMID:23497566). The variant was observed in homozygous state in a male patient with disease onset at age 30, who had gait disturbance, nystagmus, slight dysmetria, no dysarthria, no pyramidal damage, and urge incontinence. MRI revealed minor atrophy of the superior cerebellar vermis, an arachnoid cyst, and a thinning of the posterior mid-body of the corpus callosum. The p.Thr458Ile variant was also found in compound heterozygous  state (with p.Val995Phe) in a male patient with disease onset at age 20, whose symptoms comprised an early-onset triad of cerebellar ataxia, pyramidal tract signs (bilateral spasticity and extensorplantar response) and peripheral sensorimotor neuropathy. This patient had gait ataxia, cerebellar oculomotor disturbance, dysarthria, dysphagia, intention tremor, dysmetria, and spasiticity (Synofzik_2013_PMID:23497566). The variant was also observed in 14/3500 control chromosomes (heterozygous) (Synofzik_2013_PMID:23497566). The p.Thr458Ile variant was also observed in compound heterozygous state (with a 1.5 Mb macrodeletion), with teenage-onset disease, with severe cerebellar ataxia, mild spasticity, mild peripheral neuropathy, and abnormal fundoscopy (Romano_2012_PMID: 23280630). The p.Thr458Ile variant in compound heterozygous state (in trans with p.Pro2798Gln) in a female patient with multifocal myoclonus (onset 13 years old), tonic clonic seizures (onset 15 years old) as well as additional seizure types, cognitive decline, pyramidal signs, and cerebellar ataxia; the variant was considered likely pathogenic (Nascimento_2016_PMID:27433545). The p.Thr458Ile variant was found in compound heterozygous state (with p.Val995Phe) in a patient with moderate to severe gait ataxia, spasticity, and atrophy of cerebellar vermis with an age of onset before 20 years, and considered pathogenic (Kreuz_2010_Medizinische Genetik 1 Conference Abstracts 2010). The variant was identified in control databases in 720 of 282826 chromosomes (1 homozygous) at a frequency of 0.002546 (Genome Aggregation Database Feb 27, 2017). The variant was identified in dbSNP (rs61729954), ClinVar (Conflicting interpretations of pathogenicity. Uncertain significance [4], benign [2]. The variant was identified in the following populations: Ashkenazi Jewish in 233 of 10370 chromosomes (freq: 0.02247), Other in 32 of 7224 chromosomes (freq: 0.00443), European (non-Finnish) in 352 of 129148 chromosomes (freq: 0.002726), Latino in 55 of 35434 chromosomes (freq: 0.001552), South Asian in 23 of 30612 chromosomes (freq: 0.000751), European (Finnish) in 14 of 25116 chromosomes (freq: 0.000557), African in 11 of 24968 chromosomes (freq: 0.000441), but was not observed in East Asian populations. The p.Thr458 residue is conserved in mammals and other organisms. Computational analyses (SIFT, Polyphen2, MUT Assesor, DANN, MT, FATHMM, MetaLR, Revel) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogencity.  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.

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