ClinVar Miner

Submissions for variant NM_001386140.1(MTTP):c.1867+5G>A

gnomAD frequency: 0.00001  dbSNP: rs1429774833
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000015304 SCV003934384 pathogenic Abetalipoproteinaemia 2023-05-17 criteria provided, single submitter clinical testing Variant summary: MTTP c.1867+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Shoulders_1994). The variant allele was found at a frequency of 4e-06 in 251400 control chromosomes (gnomAD). c.1867+5G>A has been reported in the literature in multiple individuals affected with Abetalipoproteinaemia (examples: Narcisi_1995 and Shoulders_1993 ). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 8533758, 8111381). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003556024 SCV004293204 likely pathogenic not provided 2023-02-13 criteria provided, single submitter clinical testing This sequence change falls in intron 14 of the MTTP gene. It does not directly change the encoded amino acid sequence of the MTTP protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has been observed in individual(s) with abetalipoproteinemia (PMID: 8111381). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14236). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 15 and introduces a premature termination codon (PMID: 8111381). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000015304 SCV000035563 pathogenic Abetalipoproteinaemia 1993-12-01 no assertion criteria provided literature only

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