GRCh38/hg38 6q21(chr6:106539306-106649299)x1 AND Optic atrophy 10 with or without ataxia, intellectual disability, and seizures

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 24, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003327619.2

Allele description [Variation Report for GRCh38/hg38 6q21(chr6:106539306-106649299)x1]

GRCh38/hg38 6q21(chr6:106539306-106649299)x1

Genes:

LOC129996910:ATAC-STARR-seq lymphoblastoid active region 24892 [Gene]
LOC129996911:ATAC-STARR-seq lymphoblastoid active region 24893 [Gene]
LOC129389600:MPRA-validated peak6003 silencer [Gene]
LOC123775393:Sharpr-MPRA regulatory region 441 [Gene]
CRYBG1:crystallin beta-gamma domain containing 1 [Gene - OMIM - HGNC]
QRSL1:glutaminyl-tRNA amidotransferase subunit QRSL1 [Gene - OMIM - HGNC]
RTN4IP1:reticulon 4 interacting protein 1 [Gene - OMIM - HGNC]

Variant type:

copy number loss

Cytogenetic location:

6q21

Genomic location:

Chr6: 106539306 - 106649299 (on Assembly GRCh38)

Preferred name:

GRCh38/hg38 6q21(chr6:106539306-106649299)x1

HGVS:

Condition(s)

Name:: Optic atrophy 10 with or without ataxia, intellectual disability, and seizures (OPA10)
Synonyms:: Optic atrophy 10 with or without ataxia, mental retardation, and seizures; OPTIC ATROPHY 10 WITH OR WITHOUT ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND SEIZURES
Identifiers:: MONDO: MONDO:0020737; MedGen: C4225227; OMIM: 616732

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004034270	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG/ClinGen CNV Guidelines, 2019)	Likely pathogenic (Aug 24, 2023)	maternal	research	PubMed (2) [See all records that cite these PMIDs] 31690835, 33037779

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004034270

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG/ClinGen CNV Guidelines, 2019)

Likely pathogenic
(Aug 24, 2023)

maternal

research

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	maternal	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen).

Riggs ER, Andersen EF, Cherry AM, Kantarci S, Kearney H, Patel A, Raca G, Ritter DI, South ST, Thorland EC, Pineda-Alvarez D, Aradhya S, Martin CL.

Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6. Erratum in: Genet Med. 2021 Nov;23(11):2230. doi: 10.1038/s41436-021-01150-9.

PubMed [citation]

PMID:: 31690835
PMCID:: PMC7313390

Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis.

D'Gama AM, England E, Madden JA, Shi J, Chao KR, Wojcik MH, Torres AR, Tan WH, Berry GT, Prabhu SP, Agrawal PB.

Am J Med Genet A. 2021 Jan;185(1):203-207. doi: 10.1002/ajmg.a.61910. Epub 2020 Oct 9.

PubMed [citation]

PMID:: 33037779
PMCID:: PMC8388561

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV004034270.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

Description

A confirmed maternally inherited heterozygous deletion of 5 genes (https://genescout.omim.org/), including RTN4IP1, was identified by exome sequencing in one individual with optic atrophy in the compound heterozygous state, along with a variant of uncertain significance (p.Val88Gly) (Variation ID: 916015), ([GRCh 38] chr6:106539306_106649299x1) (PMID: 33037779). These breakpoints have been estimated by exome sequencing only and therefore may not reflect the true breakpoints. The patient phenotype is nonspecific, but is consistent with cases described in the literature and/or published databases with overlapping variants. There are no known haploinsufficient genes contained within the deleted region, however loss of function of RTN4IP1 is an established disease mechanism in autosomal recessive optic atrophy with or without ataxia, intellectual disability, and seizures (https://search.thegencc.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive optic atrophy. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1: 0 points, 2: 0.90 points, 3: 0 points, 4-5: 0.08 points; Total: 0.98 points; Riggs 2020 (PMID: 31690835).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 30, 2024

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