Submissions for variant NM_014363.6(SACS):c.4466A>G (p.Asn1489Ser)

gnomAD frequency: 0.00521  dbSNP: rs147099630

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193608	SCV000248786	benign	not specified	2019-08-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475223	SCV000562822	benign	Spastic paraplegia	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000193608	SCV000704701	benign	not specified	2016-12-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000709972	SCV001138917	likely benign	Charlevoix-Saguenay spastic ataxia	2019-05-28	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000193608	SCV001476820	benign	not specified	2020-03-24	criteria provided, single submitter	clinical testing
Pars Genome Lab	RCV000709972	SCV001652855	likely benign	Charlevoix-Saguenay spastic ataxia	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000709972	SCV001737291	likely benign	Charlevoix-Saguenay spastic ataxia	2021-06-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001358184	SCV001906941	benign	not provided	2018-10-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26539891, 27980752)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000193608	SCV002050976	likely benign	not specified	2021-12-10	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847872	SCV002105043	benign	Hereditary spastic paraplegia	2021-04-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001358184	SCV004136811	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	SACS: BP4, BS1, BS2
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000454342	SCV000537975	likely pathogenic	Abnormal brain morphology		flagged submission	research
GenomeConnect, ClinGen	RCV000709972	SCV000840336	not provided	Charlevoix-Saguenay spastic ataxia		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV000709972	SCV001463616	benign	Charlevoix-Saguenay spastic ataxia	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358184	SCV001553855	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SACS p.Asn1342Ser variant was not identified in the literature nor was it identified in Cosmic, MutDB, and LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs147099630) as "With Likely pathogenic allele". In ClinVar, there are five submissions with conflicting interpretations of pathogenicity: likely pathogenic (Lupski Lab, Baylor-Hopkins CMG,Baylor College of Medicine), benign (Invitae and EGL Genetic Diagnostics) and uncertain significance (Genetic Services Laboratory, University of Chicago). The associated conditions are: Spastic ataxia Charlevoix-Saguenay type, abnormality of brain morphology, and Spastic paraplegia. The variant was identified in control databases in 2472 of 278622 chromosomes (33 homozygous) at a frequency of 0.008872 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 440 of 10136 chromosomes (freq: 0.04341), South Asian in 924 of 29334 chromosomes (freq: 0.0315), Other in 66 of 7086 chromosomes (freq: 0.009314), European (non-Finnish) in 880 of 127810 chromosomes (freq: 0.006885), while the variant was not observed in the Latino, European (Finnish), African, and East Asian populations. The variant was also identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016). The p.Asn1342 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) do not suggest a high likelihood of impact to the protein. MutationTaster predicts an impact to the protein. However, all this information is not predictive enough to rule out pathogenicity. 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001358184	SCV001929724	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001358184	SCV001970575	likely benign	not provided		no assertion criteria provided	clinical testing