ClinVar Miner

Submissions for variant NM_020919.4(ALS2):c.3415C>T (p.Arg1139Ter) (rs767350733)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624087 SCV000742272 pathogenic Inborn genetic diseases 2017-03-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Foundation for Research in Genetics and Endocrinology,Institute of Human Genetics RCV000735438 SCV000844956 pathogenic Amyotrophic lateral sclerosis type 2 2018-10-23 no assertion criteria provided clinical testing The observed variant c.3415C>T (p.Arg1139Ter) has not been reported in 1000 Genomes and has a minor allele frequency of 0.002% in the ExAC databases. The in silico prediction of the given variant is damaging by MutationTaster2.
GeneDx RCV000421128 SCV000536575 likely pathogenic not provided 2017-01-31 criteria provided, single submitter clinical testing The R1139X variant in the ALS2 gene has been reported previously in the compound heterozygous state, opposite of a second ALS2 variant, in two siblings with progressive spastic paraplegia, macrocephaly, speech and language delays, and abnormal findings on brain MRI (Vanderver et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R1139X variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret R1139X as a likely pathogenic variant.

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