NM_152443.3(RDH12):c.716G>T (p.Arg239Leu) AND Leber congenital amaurosis

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jul 22, 2024
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:: RCV001835041.2

Allele description [Variation Report for NM_152443.3(RDH12):c.716G>T (p.Arg239Leu)]

NM_152443.3(RDH12):c.716G>T (p.Arg239Leu)

Genes:

GPHN:gephyrin [Gene - OMIM - HGNC]
RDH12:retinol dehydrogenase 12 [Gene - OMIM - HGNC]
ZFYVE26:zinc finger FYVE-type containing 26 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q24.1

Genomic location:

Preferred name:

NM_152443.3(RDH12):c.716G>T (p.Arg239Leu)

HGVS:

NC_000014.9:g.67729248G>T
NG_008321.1:g.32363G>T
NM_152443.3:c.716G>TMANE SELECT
NP_689656.2:p.Arg239Leu
NC_000014.8:g.68195965G>T
NM_152443.2:c.716G>T

Protein change:

R239L

Links:

dbSNP: rs1239043055

NCBI 1000 Genomes Browser:

rs1239043055

Molecular consequence:

NM_152443.3:c.716G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Leber congenital amaurosis (LCA)
Synonyms:: Congenital retinal blindness; Leber's amaurosis
Identifiers:: MONDO: MONDO:0018998; MeSH: D057130; MedGen: C0339527; OMIM: PS204000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002091286	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Oct 7, 2021)	germline	clinical testing
SCV005203027	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jul 22, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 31456290, 35006499, 37217489, 37714431, 32141364 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002091286

Natera, Inc.

no assertion criteria provided

Likely pathogenic
(Oct 7, 2021)

germline

clinical testing

SCV005203027

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jul 22, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC).

Sharon D, Ben-Yosef T, Goldenberg-Cohen N, Pras E, Gradstein L, Soudry S, Mezer E, Zur D, Abbasi AH, Zeitz C, Cremers FPM, Khan MI, Levy J, Rotenstreich Y, Birk OS, Ehrenberg M, Leibu R, Newman H, Shomron N, Banin E, Perlman I.

Hum Mutat. 2020 Jan;41(1):140-149. doi: 10.1002/humu.23903. Epub 2019 Sep 15.

PubMed [citation]

PMID:: 31456290

Associations Between Fundus Types and Clinical Manifestations in Patients with RDH12 Gene Mutations.

Jin J, Liang L, Jin K, Zhang HJ, Liu R, Shen Y.

Brain Topogr. 2022 Jul;35(4):525-535. doi: 10.1007/s10548-021-00885-7. Epub 2022 Jan 10.

PubMed [citation]

PMID:: 35006499

See all PubMed Citations (5)

Details of each submission

From Natera, Inc., SCV002091286.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005203027.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: RDH12 c.716G>T (p.Arg239Leu) results in a non-conservative amino acid change in 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 4e-06 in 248206 control chromosomes. c.716G>T has been reported in the literature in homozygous or compound heterozygous individuals affected with Leber Congenital Amaurosis (e.g. Schlottmann_2023, Daich Varela_2024, Jin_2022, Sharon_2020, Zanolli_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37714431, 35006499, 37217489, 31456290, 32141364). ClinVar contains an entry for this variant (Variation ID: 536988). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Sep 29, 2024

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