rs1064793252

Positions:

• chr1-8358216-T-TGGTGGA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1 PM2 PP3 PP5_Very_Strong BP3

The NM_001042681.2(RERE):​c.4318_4319insTCCACC​(p.Leu1438_His1439dup) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RERE NM_001042681.2 inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.97

Genes affected

RERE (HGNC:9965): (arginine-glutamic acid dipeptide repeats) This gene encodes a member of the atrophin family of arginine-glutamic acid (RE) dipeptide repeat-containing proteins. The encoded protein co-localizes with a transcription factor in the nucleus, and its overexpression triggers apoptosis. A similar protein in mouse associates with histone deacetylase and is thought to function as a transcriptional co-repressor during embryonic development. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_001042681.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 1-8358216-T-TGGTGGA is Pathogenic according to our data. Variant chr1-8358216-T-TGGTGGA is described in ClinVar as [Pathogenic]. Clinvar id is 418456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP3: Nonframeshift variant in repetitive region in NM_001042681.2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RERE	NM_001042681.2	c.4318_4319insTCCACC	p.Leu1438_His1439dup	inframe_insertion	20/23	ENST00000400908.7
RERE	NM_001042682.2	c.2656_2657insTCCACC	p.Leu884_His885dup	inframe_insertion	10/13
RERE	NM_012102.4	c.4318_4319insTCCACC	p.Leu1438_His1439dup	inframe_insertion	21/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RERE	ENST00000400908.7	c.4318_4319insTCCACC	p.Leu1438_His1439dup	inframe_insertion	20/23	1	NM_001042681.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 19, 2022	- -
Pathogenic, no assertion criteria provided	research	Sbielas Lab-Department of Human Genetics University of Michigan, University of Michigan Medical School	Oct 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Sep 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (MIM#616975). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated Atrophin-1 domain (PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as de novo in multiple individuals with CHARGE-like syndrome (PMIDs: 27087320, 29300383, 29330883) and as pathogenic in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

CHARGE syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

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- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2018

The apparently de novo c.4313_4318dupTCCACC variant in the RERE gene has been reported previously as de novo in an individual with microcephaly, developmental delay, short stature, congenital heart defects, unilateral iris coloboma, choanal atresia, cryptorchidism, thin corpus callosum and ventriculomegaly (Fregeau et al., 2016). The c.4313_4318dupTCCACC variant represents the in-frame duplication of two amino acids, Leucine 1438 and Histidine 1439, denoted p.Leu1438_His1439dup. The duplicated residues are well conserved across species. The c.4313_4318dupTCCACC variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common variant in these populations. Therefore, we now interpret c.4313_4318dupTCCACC as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064793252; hg19: chr1-8418276;