Submissions for variant NM_006846.4(SPINK5):c.2471_2474del (p.Lys824fs)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV005059032	SCV003031837	pathogenic	Ichthyosis linearis circumflexa	2024-06-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys824Argfs*99) in the SPINK5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPINK5 are known to be pathogenic (PMID: 11511292, 11841556). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Netherton syndrome (PMID: 32533806). This variant is also known as chr5:147499882_147499885delAAAG (p.Lys824ArgfsTer117). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV002776177	SCV004013506	pathogenic	Netherton syndrome		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with SPINK5 related disorder (PMID: 32533806). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV004721087	SCV005327800	pathogenic	not provided	2023-12-28	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32533806)