rs267606821

Positions:

chr1-212859026-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The ENST00000366971.9(FLVCR1):c.574T>C(p.Cys192Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,612,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

FLVCR1
ENST00000366971.9 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 1.92

Variant links:

Genes affected

FLVCR1 (HGNC:24682): (FLVCR choline and heme transporter 1) This gene encodes a member of the major facilitator superfamily of transporter proteins. The encoded protein is a heme transporter that may play a critical role in erythropoiesis by protecting developing erythroid cells from heme toxicity. This gene may play a role in posterior column ataxia with retinitis pigmentosa and the hematological disorder Diamond-Blackfan syndrome. [provided by RefSeq, Jan 2011]

FLVCR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.962

PP5

Variant 1-212859026-T-C is Pathogenic according to our data. Variant chr1-212859026-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLVCR1	NM_014053.4 linkuse as main transcript	c.574T>C	p.Cys192Arg	missense_variant	1/10	ENST00000366971.9	NP_054772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLVCR1	ENST00000366971.9 linkuse as main transcript	c.574T>C	p.Cys192Arg	missense_variant	1/10	1	NM_014053.4	ENSP00000355938	P1	Q9Y5Y0-1
FLVCR1	ENST00000419102.1 linkuse as main transcript	c.112T>C	p.Cys38Arg	missense_variant	1/9	5		ENSP00000414680

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250562

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135466

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1459952

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725896

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000991

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Posterior column ataxia-retinitis pigmentosa syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 07, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 12, 2010	- -
Likely pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The FLVCR1 c.574T>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PM3, PP1-S. Based on this evidence we have classified this variant as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 25, 2022	Variant summary: FLVCR1 c.574T>C (p.Cys192Arg) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250562 control chromosomes (gnomAD). c.574T>C has been reported in the literature as a biallelic genotype in individuals affected with Posterior Column Ataxia-Retinitis Pigmentosa Syndrome (Rajadhyaksha_2010, Chiabrando_2016). These data indicate that the variant is likely to be associated with disease. At least one publication reports in vitro experimental evidence evaluating an impact on protein function: the variant protein failed to traffick to the plasma membrane and cells expressing the variant had reduced heme-exporting capability, resulting in increased susceptibility to heme-toxicity (Yanatori_2012). One ClinVar submitter has assessed the variant since 2014: the variant was classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2023	Published functional studies demonstrate the C192R variant reduced ability to export heme, increased heme toxicity, and reduced half life compared to wild type indicating instability of the C192R protein (PMID: 22483575); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21267618, 28766925, 24628582, 23506900, 24782769, 27923065, 21070897, 29192808, 31964843, 32466579, 37469134, 36917984, 37808796, 22483575, Ha2023[preprint]) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 16, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FLVCR1 function (PMID: 22483575). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FLVCR1 protein function. ClinVar contains an entry for this variant (Variation ID: 18420). This missense change has been observed in individual(s) with FLVCR1-related conditions (PMID: 21070897, 27923065; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs267606821, gnomAD 0.003%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 192 of the FLVCR1 protein (p.Cys192Arg). -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

The c.574T>C (p.C192R) alteration is located in exon 1 (coding exon 1) of the FLVCR1 gene. This alteration results from a T to C substitution at nucleotide position 574, causing the cysteine (C) at amino acid position 192 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of <0.01% (5/250562) total alleles studied. The highest observed frequency was <0.01% (4/113176) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state and as compound heterozygous in trans with another pathogenic FLVCR1 alteration in unrelated individuals with FLVCR1-related hereditary sensory and autonomic neuropathy (Rajadhyaksha ,2010; Chiabrando, 2016). In addition, this alteration has been found to segregate with FLVCR1-related hereditary sensory and autonomic neuropathy among multiple individuals in one family (Rajadhyaksha, 2010). This amino acid position is not well conserved in available vertebrate species. FLVCR1 p.C192R lacked heme export activity, elicited cellular damage by accumulated heme and was significantly more sensitive to heme toxicity compared to wild-type (Yanatori, 2012). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.91

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0080

Polyphen

0.99

Vest4

0.87

MutPred

0.82

Loss of methylation at K191 (P = 0.0189);

MVP

1.0

MPC

2.6

ClinPred

0.99

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over