Submissions for variant NM_006846.4(SPINK5):c.1964G>A (p.Gly655Asp)

gnomAD frequency: 0.00313  dbSNP: rs142227576

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486022	SCV000565592	uncertain significance	not provided	2020-11-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV003762745	SCV000631292	likely benign	Ichthyosis linearis circumflexa	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001084675	SCV001313104	likely benign	Netherton syndrome	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001084675	SCV002495973	uncertain significance	Netherton syndrome	2021-05-04	criteria provided, single submitter	clinical testing	SPINK5 NM_006846.3 exon 21 p.Gly655Asp (c.1964G>A):This variant has not been reported in the literature but is present in 0.4% (329/68022) of European alleles including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-148114438-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:418504). This variant amino acid Aspartic acid (Asp) is present in several bird species; this suggests that this variant may not impact the protein. However, additional computational prediction tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV000486022	SCV004157292	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003915327	SCV004736214	likely benign	SPINK5-related disorder	2020-06-10	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).