ClinVar Miner

Submissions for variant NM_006846.3(SPINK5):c.2468del (p.Lys823fs) (rs565782662)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000627412 SCV000748407 pathogenic not provided 2018-04-10 criteria provided, single submitter clinical testing The c.2468delA pathogenic variant in the SPINK5 gene has been reported previously in individuals with Netherton syndrome, including in at least one individual who had a pathogenic variant on the opposite SPINK5 allele (in trans) (Bitoun et al., 2002; Ilias et al., 2015). The c.2468delA variant causes a frameshift starting with codon Lysine 823, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 101 of the new reading frame, denoted p.Lys823ArgfsX101. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2468delA variant is observed in 79/14,576 (0.54%) alleles from individuals of South Asian background in large population cohorts (Lek et al., 2016). We interpret c.2468delA as a pathogenic variant.
Reproductive Health Research and Development,BGI Genomics RCV000991162 SCV001142348 pathogenic Netherton syndrome 2020-01-06 no assertion criteria provided curation NM_006846.3:c.2468delA in the SPINK5 gene has an allele frequency of 0.005 in South subpopulation in the gnomAD database. This variant has been reported previously in individuals with Netherton syndrome, including one compound heterozygote 1608-1G>A/2468delA and one homozygote (PMID: 11841556). The c.2468delA variant causes a frameshift starting with codon Lysine 823, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 101 of the new reading frame, denoted p.Lys823Argfs*101. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PVS1; PM3; PP4.

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