NM_000180.4(GUCY2D):c.935C>T (p.Thr312Met) AND Leber congenital amaurosis 1

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Sep 1, 2022
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:: RCV001250818.3

Allele description [Variation Report for NM_000180.4(GUCY2D):c.935C>T (p.Thr312Met)]

NM_000180.4(GUCY2D):c.935C>T (p.Thr312Met)

Gene:

GUCY2D:guanylate cyclase 2D, retinal [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000180.4(GUCY2D):c.935C>T (p.Thr312Met)

Other names:

NM_000180.4(GUCY2D):c.935C>T

HGVS:

NC_000017.11:g.8004065C>T
NG_009092.1:g.6396C>T
NM_000180.4:c.935C>TMANE SELECT
NP_000171.1:p.Thr312Met
NP_000171.1:p.Thr312Met
NC_000017.10:g.7907383C>T
NM_000180.3:c.935C>T
Q02846:p.Thr312Met

Protein change:

T312M

Links:

UniProtKB: Q02846#VAR_067171; dbSNP: rs61749673

NCBI 1000 Genomes Browser:

rs61749673

Molecular consequence:

NM_000180.4:c.935C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Leber congenital amaurosis 1 (LCA1)
Synonyms:: AMAUROSIS CONGENITA OF LEBER I; RETINAL BLINDNESS, CONGENITAL; Congenital absence of the rods and cones; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008764; MedGen: C2931258; Orphanet: 65; OMIM: 204000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001426303	Laboratory of Genetics in Ophthalmology, Institut Imagine	no assertion criteria provided	Likely pathogenic	inherited	research	PubMed (1) [See all records that cite this PMID]
SCV002572926	3billion, Medical Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15691574, 26047050, 17964524, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001426303

Laboratory of Genetics in Ophthalmology, Institut Imagine

no assertion criteria provided

Likely pathogenic

inherited

research

PubMed (1)
[See all records that cite this PMID]

SCV002572926

3billion, Medical Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 1, 2022)

germline

clinical testing

PubMed (4)
[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	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	inherited	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Evaluation of genotype-phenotype associations in leber congenital amaurosis.

Galvin JA, Fishman GA, Stone EM, Koenekoop RK.

Retina. 2005 Oct-Nov;25(7):919-29.

PubMed [citation]

PMID:: 16205573

Clinical phenotypes in carriers of Leber congenital amaurosis mutations.

Galvin JA, Fishman GA, Stone EM, Koenekoop RK.

Ophthalmology. 2005 Feb;112(2):349-56.

PubMed [citation]

PMID:: 15691574

See all PubMed Citations (5)

Details of each submission

From Laboratory of Genetics in Ophthalmology, Institut Imagine, SCV001426303.1

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

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

From 3billion, Medical Genetics, SCV002572926.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.60). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GUCY2D-related disorder (ClinVar ID: VCV000098610 / PMID: 15691574 , 26047050 / 3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset). Different missense changes at the same codon (p.Thr312Arg, p.Thr312Pro) have been reported to be associated with GUCY2D-related disorder (PMID: 17964524 , 26047050). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Mar 5, 2025

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