rs374128662
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_014363.6(SACS):c.814C>T(p.Arg272Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R272H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_014363.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SACS | NM_014363.6 | c.814C>T | p.Arg272Cys | missense_variant | 8/10 | ENST00000382292.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SACS | ENST00000382292.9 | c.814C>T | p.Arg272Cys | missense_variant | 8/10 | 5 | NM_014363.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251440Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135888
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461886Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8AN XY: 727242
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
Charlevoix-Saguenay spastic ataxia Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 13, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 24, 2019 | Variant summary: SACS c.814C>T (p.Arg272Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 246202 control chromosomes. c.814C>T has been reported in the literature in multiple individuals affected with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay and in families with segregation data (Guernsey_2010, Thiffaul_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 09, 2023 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 13, 2020 | Published functional studies demonstrate a damaging effect (Lariviere et al., 2019); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30866998, 23250129, 30901567, 29945973, 31493945, 19892370, 23280630) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 06, 2023 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 30866998, 29945973). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. - |
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 272 of the SACS protein (p.Arg272Cys). This variant is present in population databases (rs374128662, gnomAD 0.003%). This missense change has been observed in individual(s) with SACS-related conditions (PMID: 19892370, 30901567). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SACS protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary ataxia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 28, 2016 | The p.Arg272Cys variant in SACS has been reported in 2 individuals with ataxia a nd segregated with the disease in 3 affected individuals from each family. Affec ted members from one of the families were homozygous whereas affected individual s from the other family were compound heterozygous (Guernsey 2010), while unaffe cted individuals were all heterozygous or did not have the p.Arg272Cys variant. The variant has been identified in 1/8600 European American chromosomes by the N HLBI Exome Sequencing Project and was absent from >60,000 individuals in the ExA C database (http://evs.gs.washington.edu/EVS/; http://exac.broadinstitute.org/; dbSNP rs374128662). Although this variant has been seen in the general populatio n, its frequency is low enough to be consistent with a recessive carrier frequen cy. Computational prediction tools and conservation analysis suggest that the p. Arg272Cys variant may impact the protein, though this information is not predict ive enough to determine pathogenicity. In summary, although additional studies a re required to fully establish its clinical significance, the p.Arg272Cys varian t is likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at