Submissions for variant NM_025132.4(WDR19):c.490G>A (p.Val164Ile)

gnomAD frequency: 0.00051  dbSNP: rs199514431

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001561180	SCV001159723	uncertain significance	not provided	2020-01-13	criteria provided, single submitter	clinical testing	The WDR19 c.490G>A; p.Val164Ile variant (rs199514431), to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is found in the general population with an overall allele frequency of 0.03% (85/280312 alleles) in the Genome Aggregation Database. The valine at codon 164 is moderately conserved, it occurs as an isoleucine in multiple vertebrate species, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Val164Ile variant is uncertain at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001044749	SCV001208564	uncertain significance	Asphyxiating thoracic dystrophy 5; Senior-Loken syndrome 8	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 164 of the WDR19 protein (p.Val164Ile). This variant is present in population databases (rs199514431, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with WDR19-related conditions. ClinVar contains an entry for this variant (Variation ID: 811687). 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 WDR19 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.
Illumina Laboratory Services, Illumina	RCV001150370	SCV001311431	uncertain significance	Cranioectodermal dysplasia 4	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.
Illumina Laboratory Services, Illumina	RCV001150371	SCV001311432	uncertain significance	Asphyxiating thoracic dystrophy 5	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.
GeneDx	RCV001561180	SCV001783726	uncertain significance	not provided	2020-09-18	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV001819714	SCV002064870	uncertain significance	not specified	2018-02-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005029561	SCV005662188	uncertain significance	Asphyxiating thoracic dystrophy 5; Nephronophthisis 13; Cranioectodermal dysplasia 4; Senior-Loken syndrome 8; Spermatogenic failure 72	2024-01-11	criteria provided, single submitter	clinical testing