Submissions for variant NM_014363.6(SACS):c.2146C>T (p.His716Tyr)

gnomAD frequency: 0.00075  dbSNP: rs146852400

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081696	SCV000754311	benign	Spastic paraplegia	2024-12-16	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000712966	SCV000843526	benign	not provided	2018-06-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000712966	SCV000892059	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	SACS: BP4, BS2
Genome-Nilou Lab	RCV001509573	SCV001716350	benign	Charlevoix-Saguenay spastic ataxia	2021-05-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001849011	SCV002105008	likely benign	Hereditary spastic paraplegia	2020-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001356419	SCV004241938	likely benign	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: SACS c.2146C>T (p.His716Tyr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 251298 control chromosomes in the gnomAD database, including 4 homozygotes. Although this frequency is not significantly higher than estimated for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (0.0011 vs 0.0079), the healthy homozygous individuals suggest the variant is likely a benign polymorphism. To our knowledge, no occurrence of c.2146C>T in individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay and no experimental evidence demonstrating its impact on protein function have been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356419	SCV001551581	benign	not specified		no assertion criteria provided	clinical testing	The SACS p.His569Tyr variant was not identified in the literature but was identified in dbSNP (ID: rs146852400) and ClinVar (classified as benign by Invitae and Athena Diagnostics Inc and as uncertain significance by CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 295 of 282698 chromosomes (4 homozygous) at a frequency of 0.001044 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: South Asian in 109 of 30608 chromosomes (freq: 0.003561), Ashkenazi Jewish in 12 of 10364 chromosomes (freq: 0.001158), European (non-Finnish) in 148 of 129080 chromosomes (freq: 0.001147), Other in 4 of 7218 chromosomes (freq: 0.000554), European (Finnish) in 8 of 25116 chromosomes (freq: 0.000319), African in 6 of 24932 chromosomes (freq: 0.000241) and Latino in 8 of 35426 chromosomes (freq: 0.000226), but was not observed in the East Asian population. The p.His569 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000712966	SCV001800607	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000712966	SCV001971304	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945590	SCV004759788	likely benign	SACS-related disorder	2022-04-20	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).