Submissions for variant NM_015375.3(DSTYK):c.86G>A (p.Arg29Gln)

gnomAD frequency: 0.00065  dbSNP: rs200780796

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000902729	SCV001047164	likely benign	not provided	2024-01-13	criteria provided, single submitter	clinical testing
Mendelics	RCV000054500	SCV001135521	benign	Congenital anomalies of kidney and urinary tract 1	2019-05-28	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV001170058	SCV001251889	likely benign	not specified	2020-05-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000902729	SCV002062867	uncertain significance	not provided	2022-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001170058	SCV003923082	uncertain significance	not specified	2023-03-22	criteria provided, single submitter	clinical testing	Variant summary: RIPK5 (also known as DSTYK) c.86G>A (p.Arg29Gln) results in a 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 0.0009 in 252060 control chromosomes (gnomAD), predominantly at a frequency of 0.0019 within the South Asian subpopulation in the gnomAD database. c.86G>A has been reported in the literature in individuals affected with congenital abnormalities of the kidney and urinary tract (Sanna-Cherchi_2013). This report does not provide unequivocal conclusions about association of the variant with RIPK5-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
OMIM	RCV000054500	SCV000082978	pathogenic	Congenital anomalies of kidney and urinary tract 1	2013-08-15	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000902729	SCV001552961	uncertain significance	not provided		no assertion criteria provided	clinical testing	The DSTYK p.Arg29Gln variant was identified in 3 of 622 proband chromosomes (frequency: 0.0048) from individuals with congenital abnormalities of the kidney and urinary tract and was not identified in 768 control chromosomes from healthy individuals (Sanna-Cherchi_2013_PMID:23862974). The variant was identified in dbSNP (ID: rs200780796) and ClinVar (classified as likely benign by Invitae and benign by Mendelics). The variant was identified in control databases in 228 of 252060 chromosomes at a frequency of 0.0009045 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 75 of 9706 chromosomes (freq: 0.007727), South Asian in 54 of 28984 chromosomes (freq: 0.001863), European (non-Finnish) in 75 of 114366 chromosomes (freq: 0.000656), Other in 4 of 6568 chromosomes (freq: 0.000609), Latino in 19 of 33852 chromosomes (freq: 0.000561) and African in 1 of 22128 chromosomes (freq: 0.000045), but was not observed in the East Asian or European (Finnish) populations. The p.Arg29 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.