NM_152443.3(RDH12):c.236C>T (p.Ala79Val) AND Leber congenital amaurosis 13

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 18, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001919638.6

Allele description [Variation Report for NM_152443.3(RDH12):c.236C>T (p.Ala79Val)]

NM_152443.3(RDH12):c.236C>T (p.Ala79Val)

Genes:

GPHN:gephyrin [Gene - OMIM - HGNC]
RDH12:retinol dehydrogenase 12 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q24.1

Genomic location:

Preferred name:

NM_152443.3(RDH12):c.236C>T (p.Ala79Val)

HGVS:

NC_000014.9:g.67725147C>T
NG_008321.1:g.28262C>T
NM_152443.3:c.236C>TMANE SELECT
NP_689656.2:p.Ala79Val
NC_000014.8:g.68191864C>T

Protein change:

A79V

Links:

dbSNP: rs763414313

NCBI 1000 Genomes Browser:

rs763414313

Molecular consequence:

NM_152443.3:c.236C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Leber congenital amaurosis 13 (LCA13)
Identifiers:: MONDO: MONDO:0012990; MedGen: C2675186; OMIM: 612712

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002189112	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 30, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21602930, 28492532
SCV003922027	Pangenia Genomics, Pangenia Inc.	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 18, 2021)	unknown	research	PubMed (2) [See all records that cite these PMIDs] 21602930, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002189112

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 30, 2021)

germline

clinical testing

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

SCV003922027

Pangenia Genomics, Pangenia Inc.

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 18, 2021)

unknown

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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Asian	unknown	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Detection of variants in 15 genes in 87 unrelated Chinese patients with Leber congenital amaurosis.

Li L, Xiao X, Li S, Jia X, Wang P, Guo X, Jiao X, Zhang Q, Hejtmancik JF.

PLoS One. 2011;6(5):e19458. doi: 10.1371/journal.pone.0019458. Epub 2011 May 13.

PubMed [citation]

PMID:: 21602930
PMCID:: PMC3094346

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002189112.2

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

Description

This sequence change replaces alanine with valine at codon 79 of the RDH12 protein (p.Ala79Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs763414313, ExAC 0.01%). This missense change has been observed in individual(s) with Leber congenital amaurosis (PMID: 21602930). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Pangenia Genomics, Pangenia Inc., SCV003922027.1

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

Description

The RDH12, c.236C>T (p.Ala79Val) variant is at extremely low frequency in population databases; allele frequency in East Asia population is 0.0001087 by gnomAD v2.1.1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product (REVEL=0.577). This variant was found in a case with an alternate molecular basis for disease. Li et al 2011 [PMID: 21602930] reported that this heterozygous variant has been detected in a twins (LH16) affected by Leber congenital amaurosis (poor vision and nystagmus; onset from a few months after birth) with compound heterozygous deleterious variants identified in another gene CRB1.

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

Last Updated: Sep 29, 2024

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