Submissions for variant NM_006846.4(SPINK5):c.834A>C (p.Gln278His)

gnomAD frequency: 0.00004  dbSNP: rs201354872

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000291540	SCV000453746	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003761918	SCV002116005	uncertain significance	Ichthyosis linearis circumflexa	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 278 of the SPINK5 protein (p.Gln278His). This variant is present in population databases (rs201354872, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with SPINK5-related conditions. ClinVar contains an entry for this variant (Variation ID: 351520). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SPINK5 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV003168545	SCV003864341	uncertain significance	Inborn genetic diseases	2023-01-09	criteria provided, single submitter	clinical testing	The c.834A>C (p.Q278H) alteration is located in exon 10 (coding exon 10) of the SPINK5 gene. This alteration results from a A to C substitution at nucleotide position 834, causing the glutamine (Q) at amino acid position 278 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.