ClinVar Miner

Submissions for variant NM_152778.3(MFSD8):c.754+2T>A (rs587778809)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188171 SCV000241778 pathogenic not provided 2013-10-03 criteria provided, single submitter clinical testing c.754+2 T>A: IVS8+2 T>A in intron 8 of the MFSD8 gene (NM_152778.2)The c.754+2 T>A splice site mutation in the MFSD8 gene has been previously reported in affected individuals who also harbored a second MFSD8 mutation (Siintola et al., 2007; Kousi et al., 2009). This mutation destroys the canonical splice donor site in intron 8, and RT-PCR analysis of a patient who is homozygous for the c.754+2 T>A mutation revealed an altered pattern of PCR products, consistent with abnormal splicing (Siintola et al., 2007) Therefore, c.754+2 T>A is considered a pathogenic mutation. The variant is found in EPILEPSY panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000056142 SCV000447471 pathogenic Neuronal ceroid lipofuscinosis 7 2017-04-27 criteria provided, single submitter clinical testing The MFSD8 c.754+2T>A variant occurs in a canonical splice donor site and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in four studies and found in a total of 12 individuals with confirmed or suspected neuronal ceroid-lipofuscinosis, including in eight individuals (including two siblings) in a homozygous state and in four individuals in a compound heterozygous state (Siintola et al. 2007; Kousi et al. 2009; Kousi et al. 2011; Craiu et al. 2015). The c.754+2T>A variant was also reported in a heterozygous state in one unaffected parent. The variant was absent from 504 control chromosomes and not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. RT-PCR showed aberrant splicing of the variant mRNA leading to an altered pattern of products including almost complete loss of the normal transcript containing exons 7-10 of the gene (Siintola et al. 2007). Based on potential impact of splice donor variants and the evidence from the literature, the c.754+2T>A variant is classified as pathogenic for neuronal ceroid-lipofuscinosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000056142 SCV000950873 pathogenic Neuronal ceroid lipofuscinosis 7 2019-12-11 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 of the MFSD8 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in several individuals affected with MFSD8-related conditions (PMID: 17564970, 25439737, 19201763). ClinVar contains an entry for this variant (Variation ID: 65897). Experimental studies have shown that this splice donor change leads to aberrant splicing (PMID: 17564970). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MFSD8 are known to be pathogenic (PMID: 19177532). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197070 SCV001367705 pathogenic Seizures; Visual impairment 2018-12-24 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. This variant was detected in homozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197663 SCV001368442 pathogenic Spastic ataxia; Leukodystrophy; Pseudobulbar signs; Abnormality of lipid metabolism; Diabetes mellitus; Hypertensive disorder 2018-11-30 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BS1. This variant was detected in heterozygous state.
GeneReviews RCV000056142 SCV000087222 pathologic Neuronal ceroid lipofuscinosis 7 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.

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