NM_014363.6:c.1373C>T
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3BP4_StrongBS1BS2
The NM_014363.6(SACS):c.1373C>T(p.Thr458Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,614,206 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_014363.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00215 AC: 327AN: 152204Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.00264 AC: 664AN: 251426Hom.: 1 AF XY: 0.00283 AC XY: 384AN XY: 135886
GnomAD4 exome AF: 0.00213 AC: 3111AN: 1461884Hom.: 9 Cov.: 34 AF XY: 0.00216 AC XY: 1572AN XY: 727246
GnomAD4 genome AF: 0.00215 AC: 327AN: 152322Hom.: 1 Cov.: 33 AF XY: 0.00193 AC XY: 144AN XY: 74478
ClinVar
Submissions by phenotype
Charlevoix-Saguenay spastic ataxia Uncertain:4Benign:2
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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not provided Uncertain:2Benign:3
This variant is associated with the following publications: (PMID: 23497566, 27433545, 23280630, 25401298) -
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SACS: BS1, BS2 -
Hereditary spastic paraplegia Uncertain:2
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SACS-related disorder Uncertain:1
The SACS c.1373C>T variant is predicted to result in the amino acid substitution p.Thr458Ile. This variant was reported in multiple individuals with autosomal recessive hereditary spastic paraplegias (Romano et al 2013. PubMed ID: 23280630; Vural A et al 2021. PubMed ID: 33624863; Muona M et al 2014. PubMed ID: 25401298). This variant is reported in 2.2% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, which may be too common to be disease-causing. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Spastic paraplegia Benign:1
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not specified Benign:1
Variant summary: SACS c.1373C>T (p.Thr458Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 282826 control chromosomes, predominantly at a frequency of 0.022 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay phenotype (0.0079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1373C>T has been reported in the literature in individuals affected with Progressive myoclonus epilepsies, Hereditary ataxias and atypical Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (Muona_2014, Nascimento_2016, Synofzik_2013, Vural_2021). These reports do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5), benign (n=2) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at