Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001797584 | SCV002041832 | uncertain significance | not specified | 2021-11-26 | criteria provided, single submitter | clinical testing | Variant summary: PROKR2 c.629A>G (p.Gln210Arg) results in a conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251480 control chromosomes. c.629A>G has been reported in the literature as segregating in a semi-dominant mode of transmission with isolated anosmia when inherited alone and anosmia with hypogonadism when inherited as a compound heterozygote with another PROKR2 variant, c.518T>G (p.Leu173Arg) in individuals from one family that have been subsequently cited by others (example, Dode_2006, Sarfati_2013). These data indicate that the variant may be associated with disease. At least two publications report conflicting experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complete loss of PROK2 binding activity (example, Sbai_2014) while another recent study showed conflicting results with a prediction of a homozygous genotype being likely pathogenic and a heterozygous genotype being likely benign (Cox_2018). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| OMIM | RCV000022407 | SCV000043092 | pathogenic | Hypogonadotropic hypogonadism 3 with or without anosmia | 2009-01-01 | no assertion criteria provided | literature only |