ClinVar Miner

Submissions for variant NM_001127698.2(SPINK5):c.2243A>G (p.Glu748Gly) (rs181639116)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519025 SCV000616884 uncertain significance not provided 2017-08-29 criteria provided, single submitter clinical testing The E748G variant has been observed as heterozygous with no other SPINK5 variants in a single patient; the patient was published in a meeting abstract (Kumar, et al., 2009). The variant is observed in 304/66700 (0.456%) alleles from individuals of European background in the ExAC dataset, including two homozygotes (Lek et al., 2016). E748G is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000530328 SCV000631295 benign Netherton syndrome 2020-12-06 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000530328 SCV000743992 likely benign Netherton syndrome 2014-10-09 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000530328 SCV000745452 likely benign Netherton syndrome 2016-07-27 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000530328 SCV001190466 uncertain significance Netherton syndrome 2019-04-17 criteria provided, single submitter clinical testing SPINK5 NM_006846.3 exon 24 p.Glu748Gly (c.2243A>G): This variant has not been reported in the literature but is present in 0.3% (123/35358) of Latino alleles, including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-147498551-A-G). This variant is present in ClinVar (Variation ID:449103). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Clinical Services Laboratory,Illumina RCV000530328 SCV001314443 likely benign Netherton syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000530328 SCV000734387 likely benign Netherton syndrome no assertion criteria provided clinical testing
Santos-Cortez Lab,University of Colorado School of Medicine RCV001260963 SCV001338941 uncertain significance Susceptibility to nonsyndromic otitis media 2020-04-18 no assertion criteria provided research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000519025 SCV001799677 likely benign not provided no assertion criteria provided clinical testing

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