NM_152443.3(RDH12):c.139G>A (p.Ala47Thr) AND Leber congenital amaurosis

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 21, 2021
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:: RCV001420746.3

Allele description [Variation Report for NM_152443.3(RDH12):c.139G>A (p.Ala47Thr)]

NM_152443.3(RDH12):c.139G>A (p.Ala47Thr)

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.139G>A (p.Ala47Thr)

HGVS:

NC_000014.9:g.67724543G>A
NG_008321.1:g.27658G>A
NM_152443.3:c.139G>AMANE SELECT
NP_689656.2:p.Ala47Thr
NC_000014.8:g.68191260G>A
NM_152443.2:c.139G>A

Protein change:

A47T

Links:

dbSNP: rs761231974

NCBI 1000 Genomes Browser:

rs761231974

Molecular consequence:

NM_152443.3:c.139G>A - 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
SCV001623089	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 21, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26355662, 23105016, 16269441 Citation Link,
SCV002091251	Natera, Inc.	no assertion criteria provided	Pathogenic (May 5, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001623089

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 21, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV002091251

Natera, Inc.

no assertion criteria provided

Pathogenic
(May 5, 2020)

germline

clinical testing

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

Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies.

Patel N, Aldahmesh MA, Alkuraya H, Anazi S, Alsharif H, Khan AO, Sunker A, Al-Mohsen S, Abboud EB, Nowilaty SR, Alowain M, Al-Zaidan H, Al-Saud B, Alasmari A, Abdel-Salam GM, Abouelhoda M, Abdulwahab FM, Ibrahim N, Naim E, Al-Younes B, E AlMostafa A, AlIssa A, et al.

Genet Med. 2016 Jun;18(6):554-62. doi: 10.1038/gim.2015.127. Epub 2015 Sep 10.

PubMed [citation]

PMID:: 26355662

Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes.

Abu-Safieh L, Alrashed M, Anazi S, Alkuraya H, Khan AO, Al-Owain M, Al-Zahrani J, Al-Abdi L, Hashem M, Al-Tarimi S, Sebai MA, Shamia A, Ray-Zack MD, Nassan M, Al-Hassnan ZN, Rahbeeni Z, Waheeb S, Alkharashi A, Abboud E, Al-Hazzaa SA, Alkuraya FS.

Genome Res. 2013 Feb;23(2):236-47. doi: 10.1101/gr.144105.112. Epub 2012 Oct 26.

PubMed [citation]

PMID:: 23105016
PMCID:: PMC3561865

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001623089.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: RDH12 c.139G>A (p.Ala47Thr) 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 8e-06 in 251486 control chromosomes (gnomAD). c.139G>A has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis or retinal dystrophy or Retinitis pigmentosa & Rod cone dystrophy (Thompson_2005, Abu-Safieh_2013, Patel_2015). These data indicate that the variant is very likely to be associated with disease. In in vitro functional assays, the variant showed reduced ability to convert all-trans retinal to all-trans retinol exhibiting approximately 10% of wild-type activity (Thompson_2005). One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as 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

From Natera, Inc., SCV002091251.1

#	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

Last Updated: Apr 6, 2024

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