Submissions for variant NM_014908.4(DOLK):c.1257C>G (p.Ile419Met)

gnomAD frequency: 0.00016  dbSNP: rs138962748

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697187	SCV000825784	uncertain significance	DK1-congenital disorder of glycosylation	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 419 of the DOLK protein (p.Ile419Met). This variant is present in population databases (rs138962748, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DOLK-related conditions. ClinVar contains an entry for this variant (Variation ID: 575078). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DOLK protein function with a negative predictive value of 80%. 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	RCV000697187	SCV001330628	uncertain significance	DK1-congenital disorder of glycosylation	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.
Ambry Genetics	RCV002422536	SCV002678857	likely benign	Cardiovascular phenotype	2024-05-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV000697187	SCV002816064	uncertain significance	DK1-congenital disorder of glycosylation	2021-09-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000697187	SCV004563740	uncertain significance	DK1-congenital disorder of glycosylation	2023-08-31	criteria provided, single submitter	clinical testing	The DOLK c.1257C>G; p.Ile419Met variant (rs138962748), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 575078). This variant is found in the non-Finnish European population with an allele frequency of 0.02% (22/128,990 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.137). However, given the lack of clinical and functional data, the significance of the p.Ile419Met variant is uncertain at this time.
GeneDx	RCV005223126	SCV005870272	uncertain significance	not provided	2024-08-18	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25188385, 26257771)