Submissions for variant NM_014908.4(DOLK):c.631C>T (p.Arg211Cys)

gnomAD frequency: 0.00238  dbSNP: rs145310298

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723523	SCV000113611	uncertain significance	not provided	2013-06-07	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000221125	SCV000270159	likely benign	not specified	2015-07-01	criteria provided, single submitter	clinical testing	p.Arg211Cys in exon 1 of DOLK: This variant is not expected to have clinical sig nificance because it has been identified in 0.2% (162/66700) of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs145310298). Additionally, arginine (Arg) at position 211 is not conserve d in mammals or evolutionarily distant species, and 2 mammals (cape elephant shr ew and aardvark) carry a cysteine (Cys) despite high nearby amino acid conservat ion.
Illumina Laboratory Services, Illumina	RCV001086475	SCV000477557	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.
GeneDx	RCV000723523	SCV000583316	likely benign	not provided	2021-02-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23757202)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086475	SCV000638519	likely benign	DK1-congenital disorder of glycosylation	2025-02-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362729	SCV002660610	likely benign	Cardiovascular phenotype	2019-04-19	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.
CeGaT Center for Human Genetics Tuebingen	RCV000723523	SCV004032887	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	DOLK: BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000221125	SCV004122635	likely benign	not specified	2023-10-09	criteria provided, single submitter	clinical testing	Variant summary: DOLK c.631C>T (p.Arg211Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 251394 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 1.69 fold of the estimated maximal expected allele frequency for a pathogenic variant in DOLK causing DK1-Congenital Disorder Of Glycosylation (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.631C>T in individuals affected with DK1-Congenital Disorder Of Glycosylation and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; five submitters classified the variant as likely benign and one classified it as a variant of uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.