ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.6781C>A (p.Leu2261Ile) (rs146722795)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081244 SCV000289959 benign Spastic paraplegia 2020-12-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000260358 SCV000383334 uncertain significance Charlevoix-Saguenay spastic ataxia 2018-01-13 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.
Athena Diagnostics Inc RCV000516875 SCV000614973 benign not provided 2018-12-26 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000260358 SCV000743662 likely benign Charlevoix-Saguenay spastic ataxia 2014-10-09 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000260358 SCV000745005 benign Charlevoix-Saguenay spastic ataxia 2017-05-31 criteria provided, single submitter clinical testing
Natera, Inc. RCV000260358 SCV001460050 likely benign Charlevoix-Saguenay spastic ataxia 2020-01-04 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000260358 SCV001549049 uncertain significance Charlevoix-Saguenay spastic ataxia no assertion criteria provided clinical testing The p.Leu266Ile variant was identified in the proband in trans with the SACS p.Thr458Ile variant of uncertain significance. The p.Leu2261Ile variant was previously identified in the literature, in compound heterozygous state with the p.Ser527* variant in a male patient with juvenile onset motor neuropathy, ataxia, and spasticity; these variants were considered causative (Bansagi_2017_PMID:28251916). The p.Leu2261Ile variant was also identified in compound heterozygous form (with p.Ser527*) in two affected siblings with disease onset in their 40s; the variants were reported as confirmed pathogenic. Both siblings were affected by gait disturbance and cerebellar ataxia. In addition, one sibling (male) was positive for demyelinating sensorimotor neuropathy, and MRI indicated generalized atrophy. The other sibling (female) was observed to have jerky ocular pursuit and optic atrophy (Pyle_2015_PMID:25497598). The variant was identified in dbSNP (rs146722795) and ClinVar (Conflicting interpretations of pathogenicity. Uncertain significance [1], benign [2], likely benign [2]. Classified as Uncertain significance for ARSACS in 2016 by Ilumina, likely benign in 2014 by Genome Diagnostics Centre and University Medical Centre Utrecht for ARSACS, Benign for spastic paraplegia in 2017 by Erasmus Medical Centre, Benign in 2017 by Invitae, and Likely benign in 2017 by Athena Diagnostics) databases. The variant was identified in control databases in 1397 of 282308 chromosomes (8 homozygous) at a frequency of 0.004948 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 542 of 25098 chromosomes (freq: 0.0216), European (non-Finnish) in 792 of 128852 chromosomes (freq: 0.006147), Other in 27 of 7194 chromosomes (freq: 0.003753), African in 26 of 24834 chromosomes (freq: 0.001047), Latino in 10 of 35420 chromosomes (freq: 0.000282), but was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Leu266 residue is conserved in mammals and other organisms; computational analyses (MUT Assessor, SIFT, Polyphen 2, MT, FATHMM, DANN, MetaLR, Revel) predict a deleterious impact to the protein. 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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