dbSNP rs878853282: FRRS1L:p.Gly195del (chr9-109141465-ACTC-A) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong

The NM_014334.4(FRRS1L):c.584_586delGAG(p.Gly195del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000366 in 1,613,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

FRRS1L
NM_014334.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 6.08

Variant links:

Genes affected

FRRS1L (HGNC:1362): (ferric chelate reductase 1 like) This gene encodes a component of the outer-core of an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor protein in the brain. The encoded protein is thought to interact with inner-core components of the receptor, and play a role in the modulation of glutamate signaling. Mutations in this gene are associated with early infantile epileptic encephalopathy 37. [provided by RefSeq, Jul 2016]

FRRS1L links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_014334.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 9-109141465-ACTC-A is Pathogenic according to our data. Variant chr9-109141465-ACTC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-109141465-ACTC-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRRS1L	NM_014334.4 link	c.584_586delGAG	p.Gly195del	disruptive_inframe_deletion	Exon 4 of 5	ENST00000561981.5	NP_055149.3	Q9P0K9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRRS1L	ENST00000561981.5 link	c.584_586delGAG	p.Gly195del	disruptive_inframe_deletion	Exon 4 of 5	1	NM_014334.4	ENSP00000477141.2		Q9P0K9

Frequencies

GnomAD3 genomes

AF:

0.000258

AC:

AN:

151158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000487

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00231

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:

0.0000148

Gnomad OTH

AF:

0.000484

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251484

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461886

Hom.:

AF XY:

0.0000138

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000268

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000258

AC:

AN:

151276

Hom.:

Cov.:

AF XY:

0.000244

AC XY:

AN XY:

73900

show subpopulations

Gnomad4 AFR

AF:

0.0000486

Gnomad4 AMR

AF:

0.00230

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000339

Hom.:

Bravo

AF:

0.000476

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 37

Pathogenic:6

Feb 20, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FRRS1L c.584_586delGAG (p.Gly195del), also known as c.737_739delGAG (p.Gly246del), results in an in-frame deletion that is predicted to remove 1 amino acid from the DOMON domain (IPR005018) of the encoded protein. The variant allele was found at a frequency of 2e-05 in 251484 control chromosomes (gnomAD). c.584_586delGAG has been reported in the literature in multiple individuals affected with Developmental And Epileptic Encephalopathy, 37 (e.g. Madeo_2016, Abdelmoumen_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 27236917, 32928027). ClinVar contains an entry for this variant (Variation ID: 218153). Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 23, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.737_739del, results in the deletion of 1 amino acid(s) of the FRRS1L protein (p.Gly246del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has been observed in individuals with clinical features of developmental and epileptic encephalopathy (PMID: 27236917, 32928027; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218153). For these reasons, this variant has been classified as Pathogenic. -

Sep 17, 2021

New York Genome Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PM2 moderated, PM3 very strong, PM4 -

May 09, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Nov 09, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.737_739delGAG (p.G246del) alteration is located in coding exon 4 of the FRRS1L gene. This alteration consists of an in-frame deletion of 3 nucleotides between nucleotide positions 737 and 739, resulting in the deletion of a glycine at amino acid position 246. This mutation was previously reported in the homozygous state in an individual with uncoordinated gait, neurodevelopmental regression, Lennox-Gastaut syndrome, nystagmus, generalized chorea and cogwheel rigidity of her upper limbs, hyperreflexia, hypotonia, and no expressive speech (Madeo, 2016). In our internal cohort, this mutation was identified in the homozygous and compound heterozygous state in two individuals with epilepsy and developmental delay (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

FRRS1L-related disorder

Pathogenic:1

May 31, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FRRS1L c.737_739delGAG variant is predicted to result in an in-frame deletion (p.Gly246del). This variant was reported in the homozygous state in several individuals with epileptic-dyskinetic encephalopathy (Madeo et al. 2016. PubMed ID: 27236917; Abdelmoumen et al. 2020. PubMed ID: 32928027). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Feb 01, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34483011, 27236917, 32928027) -

Chorea;C0036572:Seizure;C1838578:Progressive encephalopathy

Pathogenic:1

Nov 11, 2015

Kruer lab, Phoenix Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Predicted deleterious -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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