Submissions for variant NM_012203.2(GRHPR):c.404+3_404+6del

dbSNP: rs180177309

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000186457	SCV000919477	pathogenic	Primary hyperoxaluria, type II	2018-08-03	criteria provided, single submitter	clinical testing	Variant summary: GRHPR c.404+3_404+6delAAGT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. These predictions have been confirmed by experimental evidence that this variant affects mRNA splicing (Cregeen_2003). The variant allele was found at a frequency of 2.8e-05 in 246140 control chromosomes. c.404+3_404+6delAAGT has been reported in the literature in multiple individuals affected with Primary Hyperoxaluria Type 2, and has been reported as a common pathogenic variants in individuals of Asian ancestry (Cregeen_2003, Webster_2000, Williams_2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000186457	SCV001194179	likely pathogenic	Primary hyperoxaluria, type II	2019-12-19	criteria provided, single submitter	clinical testing	NM_012203.1(GRHPR):c.404+3_404+6delAAGT is classified as likely pathogenic in the context of primary hyperoxaluria type 2. Sources cited for classification include the following: PMID 24116921 and 14635115. Classification of NM_012203.1(GRHPR):c.404+3_404+6delAAGT is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations and the incidence of disease is extremely low. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001057355	SCV001221842	pathogenic	not provided	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the GRHPR gene. It does not directly change the encoded amino acid sequence of the GRHPR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs180177309, gnomAD 0.01%). This variant has been observed in individuals with primary hyperoxaluria type 2 (PMID: 11030416, 14635115). This variant is also known as c.403_405+2delAAGT. ClinVar contains an entry for this variant (Variation ID: 204250). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in altered splicing and introduces a premature termination codon (PMID: 14635115). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000186457	SCV004191706	pathogenic	Primary hyperoxaluria, type II	2024-02-05	criteria provided, single submitter	clinical testing
GeneReviews	RCV000186457	SCV000041223	not provided	Primary hyperoxaluria, type II		no assertion provided	literature only
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000186457	SCV000239804	pathogenic	Primary hyperoxaluria, type II	2014-11-27	no assertion criteria provided	research
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000186457	SCV000239814	pathogenic	Primary hyperoxaluria, type II	2014-11-27	no assertion criteria provided	research
Natera, Inc.	RCV000186457	SCV002075675	pathogenic	Primary hyperoxaluria, type II	2021-07-02	no assertion criteria provided	clinical testing
Chinese Inherited Urolithiasis Consortium, The Affiliated Yantai Yuhuangding Hospital of Qingdao University	RCV000186457	SCV005368597	likely pathogenic	Primary hyperoxaluria, type II	2024-08-26	no assertion criteria provided	clinical testing	Variant_type:truncating/MutationTaster:NONE/CADD:NONE/phyloP:NONE/phastCons:NONE/gnomAD_exome_EastAsian:NONE/ExAC_EastAsian:NONE/dbSNP:NONE