Submissions for variant NM_014363.6(SACS):c.4076T>C (p.Met1359Thr)

gnomAD frequency: 0.00197  dbSNP: rs146451611

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000710206	SCV000225020	uncertain significance	not provided	2015-04-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000194599	SCV000248784	uncertain significance	not specified	2014-04-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515329	SCV000611517	uncertain significance	Charlevoix-Saguenay spastic ataxia	2017-05-23	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710206	SCV000614954	benign	not provided	2018-11-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000515329	SCV000915631	uncertain significance	Charlevoix-Saguenay spastic ataxia	2018-11-14	criteria provided, single submitter	clinical testing	The SACs c.4076T>C (p.Met1359Thr) missense variant has been reported in two studies in which it is found in a total of five patients with ARSACS, including in four siblings in a compound heterozygous state and in one unrelated individual in a heterozygous state with no second variant identified (Fogel et al. 2012; Palmio et al. 2016). Palmio et al. (2016) studied a Finnish family with a milder phenotype of ARSACS that presented in early adulthood. The p.Met1359Thr variant was found in trans with a double allele containing two missense variants. The three variants together segregated with disease in four affected siblings. Based on segregation analysis, the p.Met1359Thr variant was considered a disease-causing allele. Control data are unavailable for this variant which is reported at a frequency of 0.00356 in the European (non-Finnish) population of the Exome Aggregate Consortium. Based on the evidence, the p.Met1359Thr variant is classified as a variant of unknown significance but suspicious for pathogenicity for ARSACS. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082339	SCV001001471	likely benign	Spastic paraplegia	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000710206	SCV001148947	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	SACS: PP3, BS1, BS2
Mayo Clinic Laboratories, Mayo Clinic	RCV000710206	SCV001715029	uncertain significance	not provided	2022-01-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000710206	SCV001789197	likely benign	not provided	2021-06-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27980752)
Genome-Nilou Lab	RCV000515329	SCV002026650	likely benign	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847803	SCV002105036	likely benign	Hereditary spastic paraplegia	2019-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000194599	SCV003844714	likely benign	not specified	2023-02-14	criteria provided, single submitter	clinical testing	Variant summary: SACS c.4076T>C (p.Met1359Thr) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 282066 control chromosomes in the gnomAD database, including 4 homozygotes. c.4076T>C has been reported in the literature in individuals affected with adult-onset sporadic ataxia and four compound heterozygous siblings affected with a milder autosomal recessive spastic ataxia of Charlevoix-Saguenay (Fogel_2012, Palmio_2016, Lipponen_2021). These reports do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=4), likely benign (n=6) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000710206	SCV001741449	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000710206	SCV001967133	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000515329	SCV002086688	likely benign	Charlevoix-Saguenay spastic ataxia	2020-12-15	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003937553	SCV004753640	likely benign	SACS-related disorder	2023-10-30	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).