ClinVar Miner

Submissions for variant NM_025137.4(SPG11):c.2146C>T (p.Gln716Ter) (rs312262737)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000034186 SCV000260934 pathogenic Spastic paraplegia 11, autosomal recessive 2019-12-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln716*) in the SPG11 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs312262737, ExAC 0.006%). This variant has been observed in individuals affected with hereditary spastic paraplegia (PMID: 27217339, 27544499) and segregated with disease in an affected family (PMID: 20390432). Loss-of-function variants in SPG11 are known to be pathogenic (PMID: 19105190, 20110243, 22154821, 26556829). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000034186 SCV000391298 likely pathogenic Spastic paraplegia 11, autosomal recessive 2017-04-27 criteria provided, single submitter clinical testing The SPG11 c.2146C>T (p.Gln716Ter) variant is a stop gained variant that is predicted to result in prematire termination of the protein. The p.Gln716Ter variant has been reported in two studies in which it is found in a total of four patients with spastic paraplegia including in three in a homozygous state (including two siblings) and in one in a compound heterozygous state (Southgate et al. 2010; Kara et al. 2016). The p.Gln716Ter variant was also detected in a heterozygous state in the unaffected parents of the homozygous siblings (Southgate et al. 2010). The p.Gln716Ter variant was absent from 180 controls and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project. This frequency is based on one allele only but in an area of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of stop-gained variants and evidence from the literature, the p. Gln716Ter variant is classified as likely pathogenic for the autosomal recessive form of spastic paraplegia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000414282 SCV000491253 pathogenic not provided 2016-11-01 criteria provided, single submitter clinical testing The Q716X pathogenic variant in the SPG11 gene has been reported previously as a homozygous variant in twosiblings with spastic paraplegia with thin corpus callosum (HSP-TCC) (Southgate et al., 2009). It is predicted tocause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. TheQ716X variant was not observed in approximately 6,500 individuals of European and African American ancestry inthe NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
GeneReviews RCV000034186 SCV000058124 pathologic Spastic paraplegia 11, autosomal recessive 2013-01-31 no assertion criteria provided curation Converted during submission to Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000034186 SCV000747827 uncertain significance Spastic paraplegia 11, autosomal recessive 2015-11-03 no assertion criteria provided clinical testing The observed variant c.2146C>T (p.Gln716Ter) is not reported in 1000 Genomes and its minor allele frequency ExAC databases is 0.000008252. The in silico prediction of the variant is disease causing by MutationTaster2.

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