ClinVar Miner

Submissions for variant NM_001972.4(ELANE):c.597+5G>A

dbSNP: rs879253882
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236267 SCV000292548 pathogenic not provided 2021-08-19 criteria provided, single submitter clinical testing Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 10581030, 21161286, 20049848, 25502423, 23463630, 30040071, 32581362, 31321910, 21659346, 25525159)
Labcorp Genetics (formerly Invitae), Labcorp RCV001795382 SCV000644191 pathogenic Cyclical neutropenia; Neutropenia, severe congenital, 1, autosomal dominant 2024-09-20 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the ELANE gene. It does not directly change the encoded amino acid sequence of the ELANE protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with cyclic neutropenia or severe congenital neutropenia (PMID: 10581030, 20049848, 23463630, 30040071). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS4+5G>A. ClinVar contains an entry for this variant (Variation ID: 245598). 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 the last 10 residues of exon 4 (Val190-Phe199), but is expected to preserve the integrity of the reading-frame (PMID: 23463630). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV002464151 SCV002759351 pathogenic Neutropenia, severe congenital, 1, autosomal dominant 2022-12-07 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002464151 SCV005086275 pathogenic Neutropenia, severe congenital, 1, autosomal dominant 2023-07-16 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. It is hypothesied that the enzyme is no longer inhibited or properly packaged, leading to accelerated apoptosis of neutrophils (GeneReviews). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The same variant can lead to either cyclic or severe congenital neutropenia (GeneReviews). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. mRNA expression studies from affected individuals demonstrated the use of a cryptic splice site, leading to an in-frame deletion p.(Val190_Phe199del) (PMIDs: 11001877, 23463630). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten families with either cyclic or severe congenital neutropenia (PMIDs: 10581030, 11001877, 20049848, 23463630, 34340247). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM RCV000018226 SCV000038505 pathogenic Cyclical neutropenia 1999-12-01 no assertion criteria provided literature only
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003809 SCV001162258 pathogenic Neutropenia no assertion criteria provided research

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