NM_000180.4:c.121C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000180.4(GUCY2D):c.121C>T(p.Leu41Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,513,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

GUCY2D
NM_000180.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8O:1

Conservation

PhyloP100: 0.367

Variant links:

Genes affected

GUCY2D (HGNC:4689): (guanylate cyclase 2D, retinal) This gene encodes a retina-specific guanylate cyclase, which is a member of the membrane guanylyl cyclase family. Like other membrane guanylyl cyclases, this enzyme has a hydrophobic amino-terminal signal sequence followed by a large extracellular domain, a single membrane spanning domain, a kinase homology domain, and a guanylyl cyclase catalytic domain. In contrast to other membrane guanylyl cyclases, this enzyme is not activated by natriuretic peptides. Mutations in this gene result in Leber congenital amaurosis and cone-rod dystrophy-6 diseases. [provided by RefSeq, Dec 2008]

GUCY2D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2D	NM_000180.4 link	c.121C>T	p.Leu41Phe	missense_variant	Exon 2 of 20	ENST00000254854.5	NP_000171.1	Q02846
GUCY2D	XM_011523816.2 link	c.121C>T	p.Leu41Phe	missense_variant	Exon 1 of 19		XP_011522118.1	Q02846

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5 link	c.121C>T	p.Leu41Phe	missense_variant	Exon 2 of 20	1	NM_000180.4	ENSP00000254854.4		Q02846

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000120

AC:

AN:

108728

Hom.:

AF XY:

0.000149

AC XY:

AN XY:

60532

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000469

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000259

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000147

Gnomad OTH exome

AF:

0.000303

GnomAD4 exome

AF:

0.000170

AC:

231

AN:

1360890

Hom.:

Cov.:

AF XY:

0.000167

AC XY:

112

AN XY:

671144

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000263

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000171

Gnomad4 OTH exome

AF:

0.000335

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000163

Hom.:

Bravo

AF:

0.000140

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000387

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4Other:1

Jun 22, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GUCY2D c.121C>T;p.Leu41Phe variant (rs61749664) has been published in the literature in at least one individual with Leber congenital amaurosis (Perrault 2000). The variant is reported in the ClinVar database (Variation ID: 98538 ) and in the Genome Aggregation Database with an overall allele frequency of 0.01% (15/135906 alleles). The leucine at codon 41 is moderately conserved across species and computational programs (PolyPhen2, SIFT) predict this variant is tolerated. However, at least one publication indicates that this protein shows reduced function (Zulliger 2015). Considering available information, the clinical significance of this variant cannot be determined with certainty. Pathogenic GUCY2D variants are causative for autosomal dominant cone-rod dystrophy or autosomal recessive Leber congenital amaurosis (OMIM#600179). References: Perrault I et al. Spectrum of retGC1 mutations in Leber's congenital amaurosis. Eur J Hum Genet. 2000 8(8):578-82. Zulliger R et al. Impaired association of retinal degeneration-3 with guanylate cyclase-1 and guanylate cyclase-activating protein-1 leads to leber congenital amaurosis-1. J Biol Chem. 2015 290(6):3488-99. -

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 13, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in the heterozygous state in two siblings with Leber congenital amaurosis and in one family with autosomal recessive retinitis pigmentosa; none of these individuals harbored a second identifiable GUCY2D variant (Perrault et al., 2000; Vallespin et al., 2007); Published functional studies are inconclusive, with both reduced binding to RD3 protein as well as normal basal activity reported (Zulliger et al., 2015; Sharon et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31626798, 29061346, 20012162, 18055816, 10951519, 19941040, 22695961, 25477517, 31574917) -

Oct 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1

Uncertain:1

Oct 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 41 of the GUCY2D protein (p.Leu41Phe). This variant is present in population databases (rs61749664, gnomAD 0.03%). This missense change has been observed in individual(s) with Leber congenital amaurosis or autosomal recessive retinitis pigmentosa (PMID: 10951519, 15024725, 18055816, 22695961). ClinVar contains an entry for this variant (Variation ID: 98538). 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) performed at Invitae indicates that this missense variant is not expected to disrupt GUCY2D protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GUCY2D function (PMID: 11328726, 25477517). 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. -

Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1;C4551884:Choroidal dystrophy, central areolar, 1;C5231408:Night blindness, congenital stationary, type1i

Uncertain:1

Oct 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Uncertain:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-rod dystrophy 6

Uncertain:1

Feb 01, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.11

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.31

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.4

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.17

REVEL

Uncertain

0.48

Sift

Benign

0.46

Sift4G

Benign

0.28

Polyphen

0.0010

Vest4

0.72

MutPred

0.67

Loss of stability (P = 0.0927);

MVP

0.68

MPC

2.1

ClinPred

0.041

GERP RS

2.2

Varity_R

0.075

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over