ClinVar Miner

Submissions for variant NM_001099287.2(NIPAL4):c.277+5G>A

gnomAD frequency: 0.00006  dbSNP: rs376074083
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000791221 SCV001316816 uncertain significance Autosomal recessive congenital ichthyosis 6 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003387930 SCV004099986 pathogenic Lamellar ichthyosis 2023-09-19 criteria provided, single submitter clinical testing Variant summary: NIPAL4 c.277+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: Two predict the variant abolishes a canonical 5' splicing donor site, and two predict the variant weakens this site. At least one publication reports experimental evidence that this variant affects mRNA splicing, finding that it results in incorporation of part of intron 2 (Ballin_2019). The variant allele was found at a frequency of 1.3e-05 in 239084 control chromosomes (gnomAD). c.277+5G>A has been reported in the literature in individuals affected with Lamellar Ichthyosis who were compound heterozygous with another pathogenic variant (Ballin_2019). These data indicate that the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 31347739). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute for Human Genetics, University Medical Center Freiburg RCV000791221 SCV000930508 pathogenic Autosomal recessive congenital ichthyosis 6 2019-05-16 no assertion criteria provided clinical testing

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