Submissions for variant NM_022041.4(GAN):c.851+1G>A

gnomAD frequency: 0.00001  dbSNP: rs747291494

Total submissions: 6

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.
Eurofins Ntd Llc (ga)	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000763387	SCV000950717	pathogenic	Giant axonal neuropathy 1	2023-08-22	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 246282). Disruption of this splice site has been observed in individuals with clinical features of giant axonal neuropathy (Invitae). This variant is present in population databases (rs747291494, gnomAD 0.03%). For these reasons, this variant has been classified as Pathogenic. This sequence change affects a donor splice site in intron 4 of the GAN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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).
Ambry Genetics	RCV002444938	SCV002679131	likely pathogenic	Inborn genetic diseases	2021-09-02	criteria provided, single submitter	clinical testing	The c.851+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 4 of the GAN gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.