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Intellectual disability

Gene: FLVCR1

Amber List (moderate evidence)
FLVCR1 (feline leukemia virus subgroup C cellular receptor 1)
EnsemblGeneIds (GRCh38): ENSG00000162769
EnsemblGeneIds (GRCh37): ENSG00000162769
OMIM: 609144, Gene2Phenotype
FLVCR1 is in 18 panels

7 reviews

Sarah Leigh (Genomics England Curator)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510
Created: 9 Mar 2022, 3:40 p.m.
Last Modified: 9 Mar 2022, 3:40 p.m.
Panel version: 3.1510

Eleanor Williams (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Promoting this gene to amber with a recommendation for green rating following GMS review.
Created: 14 Jul 2025, 7:55 p.m. | Last Modified: 14 Jul 2025, 7:55 p.m.
Panel Version: 9.35
Associated with Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060.

Variants in this gene have been previously associated with a progressive Retinopathy-sensory neuropathy syndrome, OMIM:609033

PMID: 39306721 - Calame et al 2025 report 27 individuals from 20 families with homozygous/compound het variants in this gene (mainly missense, but also nonsense, frameshift and splice variants). 2 families from S Asia share the same variant and haplotype so could be a founder variant in the region.

13/27 individual had profound ID/DD. 3 were stillborn, and 10 others died before the age of 5, including one in the neonatal period. Severe microcephaly (Z score below -3.0) was observed in 12/27 individuals. Epilepsy was reported in 12 individuals, hypotonia in 17, spasticity in 9 (from 6 families), reduced brain volume in 19 , craniofacial malformations in 4 (those that were still born or died in neonatal period), and limb malformations in 7. An eye phenotype (Cortical visual impairment, Optic disk atrophy or Retinitis pigmentosa) was observed in 15 individuals.

All pathogenic FLVCR1 variants were rare and absent in the homozygous state in gnomAD v2.1.13. Functional studies show that pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1.

There are more than 3 cases reported with plausible disease causing variants in more than 3 cases for the intellectual disability, epilepsy, severe microcephaly, limb disorders, fetal anomalies and childhood onset hereditary spastic paraplegia panels. The gene will also be included in the Hypotonic infant superpanel through the inclusion on the Intellectual disability panel.
Created: 14 Jul 2025, 7:53 p.m. | Last Modified: 14 Jul 2025, 7:53 p.m.
Panel Version: 9.34
Comment on list classification: Leaving this gene green for now, but only one case where intellectual disability was reported. This gene should be updated at the next GMS review.
Created: 8 Oct 2020, 3:30 p.m. | Last Modified: 8 Oct 2020, 3:30 p.m.
Panel Version: 3.400
Associated with Ataxia, posterior column, with retinitis pigmentosa #609033 in OMIM. The clinical synopsis in OMIM notes that mental retardation was only see in one family.

Summary: many (~10) cases reported with varying degrees of Ataxia, posterior column, with retinitis pigmentosa but intellectual disability only reported in one case.

PMID: 30656474 - Kuehlewein et al 2019 - Six individuals with retinitis pigmentosa (RP) carrying mutations in the FLVCR1 gene underwent detailed ophthalmological examinations and two of these also an extensive neurological examination. Variants included one nonsense mutation, one 1-bp deletion, two missense variants, and one splice site variant. Mutations in FLVCR1 can present with the clinical picture of a non-syndromic autosomal recessive RP (in this case RP without PCA), RP with mild cerebellar signs, but also PCARP. No intellectual disability was reported.

PMID: 22279524 - Puffenberger et al 2012 - report a case from a Plain population from Pennsylvania (Swiss decent) where 1 individual with Posterior column ataxia with retinitis pigmentosa had a homozygous variant in FLVCR1 (c.361A>G, p.Asn121Asp), which is the same as reported in the large German-Swiss decent family by Rajadhyaksha et al 2010. No intellectual disability reported but detailed phenotype information not given.

PMID:21267618 - Ishiura et al 2011 - Japanese consanguineous family with Posterior column ataxia with retinitis pigmentosa (PCARP). Two affected siblings suffered from childhood-onset retinitis pigmentosa and slowly progressive sensory ataxia. They also showed mild mental retardation. A novel homozygous c.1477G>C (G493R) mutation in FLVCR1, cosegregated with the disease.

PMID:21070897 - Rajadhyaksha et al 2010 - from targeted sequencing of a genes in a candidate locus they report 3 families (one the family reported in Higgins et al, one French-Canadian, and one Spanish) with 3 different homozygous missense variants in FLVCR1. All affected individuals had visual problems and ataxia but no intellectual disability was reported.

PMID:9409377 - Higgins et al 1997 - report a large American pedigree of German-Swiss decent with autosomal recessive posterior column ataxia with retinitis pigmentosa. No variant data. Abstract only accessed.

Also:
PMID: 30444160 - Lee et al 2018 - Seven patients from three families were identified to have PCARP and FLVCR1 mutation. Ophthalmic features were reviewed. Abstract only accessed.
Created: 8 Oct 2020, 2:21 p.m. | Last Modified: 8 Oct 2020, 2:21 p.m.
Panel Version: 3.394

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126

Publications

Created: 8 Oct 2020, 2:21 p.m.
Last Modified: 8 Oct 2020, 2:21 p.m.
Panel version: 9.34

Zornitza Stark (Australian Genomics)

Red List (low evidence)

Progressive neurological condition, ID is not really part of the phenotype.
Created: 3 Feb 2020, 3:44 a.m. | Last Modified: 3 Feb 2020, 3:44 a.m.
Panel Version: 3.0

Phenotypes
Ataxia, posterior column, with retinitis pigmentosa, MIM#609033

Created: 3 Feb 2020, 3:44 a.m.
Last Modified: 3 Feb 2020, 3:44 a.m.
Panel version: 3.0

Caroline Wright (Sanger)

I don't know

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
ATAXIA, POSTERIOR COLUMN, WITH RETINITIS PIGMENTOSA

Publications

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_20141118_conf;in_ddg2p_20141118_conf;in_ddg2p_201507;in_ddg2p_201507_conf;in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf;in_omim_20150205_movement . Main mutation mechanism : All missense/in frame
Created: 27 Jul 2017, 5:53 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : ddg2p_20141118; ddg2p_20141118_conf; ddg2p_201507; ddg2p_201507_conf; gilissen_2014_candidate; omim_20150205_movement; Nijmegen_ID_diagnostic; GEL_ID_green_20160217; neuro_20160418_strict; All missense/in frame. This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust
Created: 19 Jul 2017, 12:28 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

Mode of pathogenicity
Other

Created: 2 Aug 2017, 5:52 p.m.

Panel version: 1.354

Lu Raymond (university of cambridge )

I don't know

Created: 23 Feb 2016, 10:05 a.m.

Panel version: 0.306

Richard Scott (Genomics England Curator)

Comment on list classification: Confirmed DD gene
Created: 7 Feb 2016, 8:31 p.m.
Created: 7 Feb 2016, 8:31 p.m.

Panel version: 0.123

History Filter Activity

14 Jul 2025, Gel status: 2

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: FLVCR1 were changed from Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126 to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126

14 Jul 2025, Gel status: 2

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: FLVCR1 were set to 30656474; 22279524; 21267618; 21070897; 9409377; 30444160; 39306721

14 Jul 2025, Gel status: 2

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: FLVCR1 were changed from ATAXIA, POSTERIOR COLUMN, WITH RETINITIS PIGMENTOSA to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126

14 Jul 2025, Gel status: 2

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: FLVCR1 were set to 21267618; 9409377; 21070897

14 Jul 2025, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: flvcr1 has been classified as Amber List (Moderate Evidence).

14 Jul 2025, Gel status: 1

Added Tag

Eleanor Williams (Genomics England Curator)

Tag Q3_25_promote_green tag was added to gene: FLVCR1.

10 Mar 2022, Gel status: 1

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review was removed from gene: FLVCR1.

9 Mar 2022, Gel status: 1

Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source Expert Review Red was added to FLVCR1. Rating Changed from Green List (high evidence) to Red List (low evidence)

8 Oct 2020, Gel status: 3

Added Tag

Eleanor Williams (Genomics England Curator)

Tag for-review tag was added to gene: FLVCR1.

8 Oct 2020, Gel status: 3

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: flvcr1 has been classified as Green List (High Evidence).

12 Mar 2018, Gel status: 3

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

7 Feb 2016, Gel status: 4

Gene classified by Genomics England curator

Richard Scott (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

7 Feb 2016, Gel status: 4

Gene classified by Genomics England curator

Richard Scott (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

FLVCR1 was created by ellenmcdonagh

13 Nov 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

FLVCR1 was added to Intellectual disabilitypanel. Sources: Expert Review Amber