Submissions for variant NM_014363.6(SACS):c.12673_12677del (p.Tyr4225fs)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471600	SCV002768989	pathogenic	Charlevoix-Saguenay spastic ataxia	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) (MIM#270550). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0253 - This variant is hemizygous. External laboratory reports this individual has a large deletion on the other allele. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0701 - Other variants predicted to result in a truncated protein and located downstream, therefore comparable to the one identified in this case, have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an individual with ARSACS (PMID: 33746006). (SP) 1201 - Variant detected in trans with a second pathogenic heterozygous variant (approximately 1.4Mb deletion that encompasses the SACS gene) in a recessive disease (analysis by an external laboratory) . (I) 1206 - This variant has been shown to be paternally inherited by an external laboratory. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV002571457	SCV003627491	pathogenic	Inborn genetic diseases	2022-07-28	criteria provided, single submitter	clinical testing	The c.12673_12677delTATCA (p.Y4225Dfs*6) alteration, located in exon 10 (coding exon 9) of the SACS gene, consists of a deletion of 5 nucleotides from position 12673 to 12677, causing a translational frameshift with a predicted alternate stop codon after 6 amino acids. This alteration occurs at the 3' terminus of the SACS gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 8% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on data from gnomAD, this allele has an overall frequency of <0.01% (2/250648) total alleles studied. The highest observed frequency was <0.01% (2/113238) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state, and in conjunction with another disease-causing SACS alteration, in multiple unrelated individuals with spastic ataxia, Charlevoix-Saguenay type (Wang, 2021; Chen, 2022). Based on the available evidence, this alteration is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003111572	SCV003784740	pathogenic	Spastic paraplegia	2023-05-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SACS protein in which other variant(s) (p.Asn4549Asp) have been determined to be pathogenic (PMID: 15156359, 21507954). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1805182). This premature translational stop signal has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 33746006). This variant is present in population databases (rs775863207, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Tyr4225Aspfs*6) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 355 amino acid(s) of the SACS protein.
GeneDx	RCV004794589	SCV005414892	likely pathogenic	not provided	2024-05-23	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in abnormal protein length as the last 355 amino acids are replaced with 5 different amino acids; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35578252, 33746006)