Cholestasis
Gene: RPGRIP1L
I agree, no specific reports of cholestasis for this gene.Created: 9 Aug 2020, 10:56 a.m. | Last Modified: 9 Aug 2020, 10:56 a.m.
Panel Version: 1.16
Both genes (TMEM67 and RPGRIP1L) are associated with a range of severe, syndromic conditions, often presenting in utero, mainly affecting kidney, or other organs than liver, including Joubert type 6, Meckel type 3, Bardet Biedl syndrome, NPHP11, RHYNS and COACH syndrome. Both genes are covered elsewhere in the following panels that match the clinical presentations: Severe paediatric disorders R14, R27, Fetal anomalies R21, Intellectual disability R29, Retinal disorders R32, Structural eye disease R36, Bardet Biedl Syndrome R107, Cystic renal disease R193, Tubulointerstitial kidney disease R202, Unexplained paediatric onset ESRD R257. Neither gene-associated classical phenotype would have cholestasis as a presenting feature, and would very likely be referred to one or more of the above alternate panels. In COACH syndrome, the presentation is syndromic, the liver involvement includes congenital hepatic fibrosis (CHF). Therefore potentially they would fit better on polycystic liver disease panel as Caroli disease (PKHD1) is commonly associated with CHF; however the testing criteria for PCLD recommends R27 (as above) or R89 Ultra-rare and atypical monogenic disorders for any complex or syndromic presentations. There is just 1 reported case with isolated CHF with 2 TMEM67 variants in the literature (PMID: 28680603) although this is very weak as 1 variant is a VUS with no supporting functional data that could be erroneous. There are no reported cases with RPGRIP1L or CC2D2A and isolated CHF. The 3rd gene associated with COACH syndrome CC2D2A was green on the 100K neonatal cholestasis panel. However looking at the evidence for the CC2D2A gene it has 2 reviews on PanelApp and was scored as red by the Bham diagnostic service and scored green by a Genomics England curator. Therefore the evidence for inclusion of these 3 COACH genes in cholestasis is limited. COACH syndrome is extremely rare with an Orphanet estimated incidence of 1 in 1,000,000. There are 34 mutations on HGMD for TMEM67 associated with COACH syndrome and just 1 mutation for RPGRIP1L. I would like to request that these 3 genes are removed from the cholestasis panel on the next update.Created: 18 May 2020, 10:44 a.m. | Last Modified: 18 May 2020, 10:44 a.m.
Panel Version: 1.4
Publications
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Congenital hepatic fibrosis
Publications
Comment on list classification: This gene has been downgraded from Green to Grey based on expert review from Miranda Durkie (Genetics).Created: 18 Aug 2020, 1:12 p.m. | Last Modified: 18 Aug 2020, 1:12 p.m.
Panel Version: 1.17
Comment on list classification: As discussed in the GMS Gastrohepatology Specialist Test Group webex call 14th Jan 2019: The Specialist Test Group agreed that there is enough evidence to rate this gene green. Promoted from amber to green.Created: 28 Jan 2019, 1:58 p.m.
Comment when marking as ready: RPGRIP1L is a causative gene of Meckel syndrome and different variants have been reported in this gene associated with this syndrome in 3+ unrelated patients (PMID:17558409, 19574260).Created: 26 Nov 2018, 2:42 p.m.
Comment on list classification: RPGRIP1L is a green gene on the Rare multisystem ciliopathy disorder panel (https://panelapp.genomicsengland.co.uk/panels/150/). It has been promoted from grey to green as it causes both Meckel syndrome (611561) and COACH syndrome (216360), which is considered by some to be a subtype of Joubert syndrome with congenital hepatic fibrosis.Created: 13 Nov 2018, 10:55 a.m.
Tag curated_removed tag was added to gene: RPGRIP1L.
Tag for-review was removed from gene: RPGRIP1L.
Gene: rpgrip1l has been removed from the panel.
Tag for-review tag was added to gene: RPGRIP1L.
Phenotypes for gene: RPGRIP1L were changed from Meckel syndrome 5 (611561); Joubert syndrome 7 (611560); COACH syndrome (216360) to Meckel syndrome 5 (611561); Joubert syndrome 7 (611560); COACH syndrome (216360); Congenital hepatic fibrosis
Publications for gene: RPGRIP1L were set to 17558409; 19574260
Gene: rpgrip1l has been classified as Green List (High Evidence).
Gene: rpgrip1l has been classified as Green List (High Evidence).
gene: RPGRIP1L was added gene: RPGRIP1L was added to Cholestasis. Sources: NHS GMS Mode of inheritance for gene: RPGRIP1L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RPGRIP1L were set to 17558409; 19574260 Phenotypes for gene: RPGRIP1L were set to Meckel syndrome 5 (611561); Joubert syndrome 7 (611560); COACH syndrome (216360)