17-8014704-C-G

Position:

• chr17-8014704-C-G

Variant summary

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

The NM_000180.4(GUCY2D):​c.2516C>G​(p.Thr839Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000493 in 1,419,722 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T839M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: GUCY2D NM_000180.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 7.91

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]

ENSG00000279174 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCY2D	NM_000180.4	c.2516C>G	p.Thr839Arg	missense_variant	13/20	ENST00000254854.5	NP_000171.1
GUCY2D	XM_011523816.2	c.2516C>G	p.Thr839Arg	missense_variant	12/19		XP_011522118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5	c.2516C>G	p.Thr839Arg	missense_variant	13/20	1	NM_000180.4	ENSP00000254854.4
ENSG00000279174	ENST00000623126.1	n.1675G>C		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251422 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000493 AC: 7 AN: 1419722 Hom.: 0 Cov.: 34 AF XY: 0.00000709 AC XY: 5 AN XY: 705578

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000461

Gnomad4 OTH exome AF: 0.0000347

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000374 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cone-rod dystrophy 6 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Sep 24, 2018

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 31, 2024

Variant summary: GUCY2D c.2516C>G (p.Thr839Arg) results in a non-conservative amino acid change located in the Haem NO binding associated (IPR011645) of 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 1.6e-05 in 251422 control chromosomes, predominantly at a frequency of 3.5e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2516C>G has been reported in the literature as a single heterozygous variant in two individuals affected with macular dystrophy and Stargardt disease, respectively (Weisschuh_2024, Hitti-Malin_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37734845, 38540785). ClinVar contains an entry for this variant (Variation ID: 635421). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 28, 2022

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 839 of the GUCY2D protein (p.Thr839Arg). This variant is present in population databases (rs61750174, gnomAD 0.004%). This missense change has been observed in individual(s) with inherited retinal dystrophy (Invitae). ClinVar contains an entry for this variant (Variation ID: 635421). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Thr839 amino acid residue in GUCY2D. Other variant(s) that disrupt this residue have been observed in individuals with GUCY2D-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.41		Loss of phosphorylation at T839 (P = 0.0252);
MVP		0.98
MPC		1.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.93
gMVP		0.99

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

Other links and lift over

dbSNP: rs61750174; hg19: chr17-7918022;