ClinVar Genomic variation as it relates to human health

Variant summary: The GRHPR c.103delG (p.Asp35ThrfsX11) variant results in a premature termination codon, predicted to cause a truncated or absent GRHPR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 62/274980 control chromosomes (gnomAD) at a frequency of 0.0002255, which does not exceed the estimated maximal expected allele frequency of a pathogenic GRHPR variant (0.0014434). Multiple publications have cited the variant in affected homozygote and compound heterozygote pts. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

The p.Asp35ThrfsX11 (NM_012203.1 c.103delG) variant in GRHPR has been reported i n at least 15 homozygous and 1 compound heterozygous individuals with primary hy peroxaluria type II, and segregated in two homozygous affected siblings from two families (Cramer 1999, Webster 2000, Johnson 2002, Cregeen 2003, Rumsby 2003). It is the most common pathogenic variant identified in Caucasian patients with t his disease (Takayama 2014). This variant has also been reported as pathogenic i n ClinVar (Variation ID#5636). The p.Asp35ThrfsX11 variant has been identified i n 21/64772 of European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs80356708), a frequency low enough to be co nsistent with carrier frequency. This variant is predicted to cause a frameshift , which alters the protein?s amino acid sequence beginning at position 35 and le ads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of fu nction of function of the GRHPR gene is an established disease mechanism in prim ary hyperoxaluria type II. In summary, the p.Asp35ThrfsX11 variant meets criteri a to be classified as pathogenic for primary hyperoxaluria type II in an autosom al recessive manner based upon its biallelic occurrence in patients with this di sease and predicted impact on protein function.

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 2 of 9). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (68 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. (ClinVar) (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. (ClinVar, PMID: 24116921) (P) 1102 - Strong phenotype match. (P) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

The GRHPR c.103delG (p.Asp35ThrfsTer11) variant results in frameshift and is predicted to result in premature termination of the protein. The p.Asp35ThrfsTer11 variant is a commonly described pathogenic variant which has been reported in at least three studies in which it was identified in at least 16 individuals diagnosed with primary hyperoxaluria, type 2. The variant was identified in a homozygous state in 14 individuals including two sets of siblings, and in a compound heterozygous state in another two individuals (Cramer et al. 1999; Cregeen et al. 2003; Rumsby et al. 2004). The variant has only been reported in individuals in Caucasian origin (Rumsby et al. 2004). The p.Asp35ThrfsTer11 variant was absent from seven controls but is reported at a frequency of 0.002111 in the African American population of the Exome Sequencing Project. The variant is also found in a homozygous state in eight individuals of the Exome Sequencing Project which could be accounted for by variable phenotypic expression from a severe early onset to asymptomatic form. Enzyme activity in patient liver biopsies has been shown to range from 0-26% of control activity (Cregeen et al. 2003; Rumsby et al. 2004). Based on the collective evidence, the c.103delG (p.Asp35ThrfsTer11) variant is classified as pathogenic for primary hyperoxaluria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

NM_012203.1(GRHPR):c.103delG(D35Tfs*11) is classified as pathogenic in the context of type 2 primary hyperoxaluria. Sources cited for classification include the following: PMID 15327387, 18560364 and 10484776. Classification of NM_012203.1(GRHPR):c.103delG(D35Tfs*11) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 16208537, 24116921, 18560364, 10484776, 31980526, 21228398, 14635115, 15327387, 11030416, 25644115, 28893421, 30609409, 31685312, 31589614)

This sequence change creates a premature translational stop signal (p.Asp35Thrfs*11) in the GRHPR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GRHPR are known to be pathogenic (PMID: 25644115). This variant is present in population databases (rs746720647, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with primary hyperoxaluria (PMID: 10484776, 15327387). ClinVar contains an entry for this variant (Variation ID: 5636). For these reasons, this variant has been classified as Pathogenic.