ClinVar Miner

Submissions for variant NM_022041.3(GAN):c.851+1G>A (rs747291494)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235982 SCV000293763 pathogenic not provided 2017-08-08 criteria provided, single submitter clinical testing The c.851+1G>A pathogenic variant in the GAN gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant has been observed in the homozygous state in several unrelated patients referred for genetic testing at GeneDx and not observed in the homozygous state in controls. This splice site variant destroys the canonical splice donor site in intron 4. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.851+1G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant is reported as pathogenic in ClinVar, but additional evidence is not available (ClinVar SCV000336956.2, SCV000603804.1; Landrum et al., 2016). We interpret c.851+1G>A as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000235982 SCV000336956 pathogenic not provided 2015-11-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506058 SCV000603804 pathogenic not specified 2017-01-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763387 SCV000894087 likely pathogenic Giant axonal neuropathy 1 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000763387 SCV000950717 pathogenic Giant axonal neuropathy 1 2019-02-22 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the GAN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs747291494, ExAC 0.03%). This variant has been observed in individuals with clinical features of giant axonal neuropathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 246282). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GAN are known to be pathogenic (PMID: 12655563, 14718689, 23890932). For these reasons, this variant has been classified as Pathogenic.

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