ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.4466A>G (p.Asn1489Ser) (rs147099630)

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Total submissions: 11
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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
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000454342 SCV000537975 likely pathogenic Abnormality of brain morphology criteria provided, single submitter research
Invitae RCV000475223 SCV000562822 benign Spastic paraplegia 2020-12-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 Inc 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
Nilou-Genome Lab RCV000709972 SCV001737291 likely benign Charlevoix-Saguenay spastic ataxia 2021-06-10 criteria provided, single submitter clinical testing
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.

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