VCV000002059.42 - ClinVar

NM_152443.3(RDH12):c.464C>T (p.Thr155Ile)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_152443.3(RDH12):c.464C>T (p.Thr155Ile)

Variation ID: 2059 Accession: VCV000002059.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q24.1 14: 67726996 (GRCh38) [ NCBI UCSC ] 14: 68193713 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 5, 2015	Oct 20, 2024	Nov 29, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_152443.3:c.464C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_689656.2:p.Thr155Ile	missense
NC_000014.9:g.67726996C>T
NC_000014.8:g.68193713C>T
NG_008321.1:g.30111C>T
	Q96NR8:p.Thr155Ile

... more HGVS ... less HGVS

Protein change

T155I

Other names

NP_689656.2:p.(Thr155Ile)

Canonical SPDI

NC_000014.9:67726995:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA252092 UniProtKB: Q96NR8#VAR_064171 OMIM: 608830.0014 dbSNP: rs121434337 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GPHN		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	757	1935
RDH12		-	-	GRCh38 GRCh37	5	627

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Leber congenital amaurosis 13	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Nov 29, 2023	RCV000002140.17
not provided	Pathogenic (1)	criteria provided, single submitter	Apr 1, 2018	RCV001091055.23
Leber congenital amaurosis	Pathogenic (2)	criteria provided, single submitter	Jul 24, 2023	RCV001826405.5
Cone-rod dystrophy	Pathogenic (1)	criteria provided, single submitter	Jul 24, 2023	RCV003324481.4
See cases	Pathogenic (1)	criteria provided, single submitter	Oct 26, 2021	RCV004584306.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 11, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 13 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367154.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3.
Pathogenic (Nov 29, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 13 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004208577.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Oct 26, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV002577891.2 First in ClinVar: Oct 08, 2022 Last updated: Jul 07, 2024	Comment: ACMG categories: PS1,PM2,PM7,PP3,PP5 Number of individuals with the variant: 1 Clinical Features: Rod-cone dystrophy (present) Zygosity: Homozygote Age: 20-29 years Sex: male Tissue: blood
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Leber congenital amaurosis 13 Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002518971.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Jul 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Leber congenital amaurosis Affected status: yes Allele origin: germline	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV004030284.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 Comment: This variant was classified as Pathogenic based on ACMG criteria: PP5, PP3, PM2, PP2.	Publications: PubMed (1) PubMed: 36909829 Comment: Clinical significance based on ACMG v2.0 Number of individuals with the variant: 4 Geographic origin: Portugal
Pathogenic (Jul 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Cone-rod dystrophy Affected status: yes Allele origin: germline	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV004030285.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 Comment: This variant was classified as Pathogenic based on ACMG criteria: PP5, PP3, PM2, PP2.	Publications: PubMed (1) PubMed: 36909829 Comment: Clinical significance based on ACMG v2.0 Number of individuals with the variant: 2 Geographic origin: Portugal
Pathogenic (Nov 24, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Leber congenital amaurosis 13 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001420497.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 16269441‚ 28157192‚ 30134391 Comment: This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 155 of the RDH12 protein (p.Thr155Ile). … (more) This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 155 of the RDH12 protein (p.Thr155Ile). This variant is present in population databases (rs121434337, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive retinal dystrophy (PMID: 16269441, 28157192, 30134391). ClinVar contains an entry for this variant (Variation ID: 2059). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RDH12 protein function. Experimental studies have shown that this missense change affects RDH12 function (PMID: 16269441). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246892.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Dec 15, 2005)	no assertion criteria provided Method: literature only	LEBER CONGENITAL AMAUROSIS 13 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022298.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 05, 2015	Publications: PubMed (1) PubMed: 16269441 Comment on evidence: In 3 patients with Leber congenital amaurosis-13 (LCA13; 612712), Thompson et al. (2005) identified a 464C-T transition in exon 5 of the RDH12 gene that … (more) In 3 patients with Leber congenital amaurosis-13 (LCA13; 612712), Thompson et al. (2005) identified a 464C-T transition in exon 5 of the RDH12 gene that resulted in a thr155-to-ile substitution (T155I). The mutation was homozygous in 2 patients and carried heterozygously on the maternal allele in the third; the paternal allele carried an H151D mutation (608830.0009). Haplotype analysis indicated that the T115I substitution is a founder mutation. (less)
Pathogenic (-)	no assertion criteria provided Method: research	Leber congenital amaurosis 13 Affected status: yes Allele origin: inherited	Laboratory of Genetics in Ophthalmology, Institut Imagine Accession: SCV001432276.1 First in ClinVar: Sep 16, 2020 Last updated: Sep 16, 2020	Publications: PubMed (1) PubMed: 16269441 Number of individuals with the variant: 2
Pathogenic (Jun 01, 2021)	no assertion criteria provided Method: clinical testing	Leber congenital amaurosis Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002091269.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
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Comment:

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 155 of the RDH12 protein (p.Thr155Ile). This variant is present in population databases (rs121434337, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive retinal dystrophy (PMID: 16269441, 28157192, 30134391). ClinVar contains an entry for this variant (Variation ID: 2059). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RDH12 protein function. Experimental studies have shown that this missense change affects RDH12 function (PMID: 16269441). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis.	Peter VG	PNAS nexus	2023	PMID: 36909829
PHENOTYPIC VARIABILITY OF RECESSIVE RDH12-ASSOCIATED RETINAL DYSTROPHY.	Zou X	Retina (Philadelphia, Pa.)	2019	PMID: 30134391
Unravelling the genetic basis of simplex Retinitis Pigmentosa cases.	Bravo-Gil N	Scientific reports	2017	PMID: 28157192
Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle.	Thompson DA	Human molecular genetics	2005	PMID: 16269441

Text-mined citations for rs121434337 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 30, 2024

ClinVar Genomic variation as it relates to human health

NM_152443.3(RDH12):c.464C>T (p.Thr155Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121434337 ...