6-42178410-A-T

Position:

• chr6-42178410-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001384910.1(GUCA1A):​c.332A>T​(p.Glu111Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E111A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GUCA1A NM_001384910.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.32

Genes affected

GUCA1A (HGNC:4678): (guanylate cyclase activator 1A) This gene encodes an enzyme that plays a role in the recovery of retinal photoreceptors from photobleaching. This enzyme promotes the activity of retinal guanylyl cyclase-1 (GC1) at low calcium concentrations and inhibits GC1 at high calcium concentrations. Mutations in this gene can cause cone dystrophy 3 and code-rod dystrophy 14. provided by RefSeq, Jul 2020]

ENSG00000290147 (HGNC:56129): (GUCA1ANB-GUCA1A readthrough) This locus represents naturally occurring readthrough transcription between the neighboring GUCA1ANB (GUCA1A neighbor) and GUCA1A (guanylate cyclase activator 1A) genes on chromosome 6. The readthrough transcript encodes the same protein as GUCA1A. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-42178410-A-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 6-42178410-A-T is Pathogenic according to our data. Variant chr6-42178410-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 962836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42178410-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCA1A	NM_001384910.1	c.332A>T	p.Glu111Val	missense_variant	2/4	ENST00000372958.2	NP_001371839.1
GUCA1ANB-GUCA1A	NM_000409.5	c.332A>T	p.Glu111Val	missense_variant	4/6		NP_000400.2
GUCA1ANB-GUCA1A	NM_001319061.2	c.332A>T	p.Glu111Val	missense_variant	4/6		NP_001305990.1
GUCA1ANB-GUCA1A	NM_001319062.2	c.332A>T	p.Glu111Val	missense_variant	3/5		NP_001305991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCA1A	ENST00000372958.2	c.332A>T	p.Glu111Val	missense_variant	2/4	1	NM_001384910.1	ENSP00000362049.1
ENSG00000290147	ENST00000654459.1	c.332A>T	p.Glu111Val	missense_variant	3/5			ENSP00000499539.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cone dystrophy 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

Jun 05, 2020

This variant is interpreted as likely pathogenic for Cone-rod dystrophy 14, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (PM1); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Well-established functional studies show a deleterious effect (PS3 downgraded to supporting); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 08, 2022

This missense change has been observed in individuals with cone-rod dystrophy (PMID: 30184081). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu111 amino acid residue in GUCA1A. Other variant(s) that disrupt this residue have been observed in individuals with GUCA1A-related conditions (PMID: 28041643; Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GUCA1A function (PMID: 30184081, 31882816). 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: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 962836). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 111 of the GUCA1A protein (p.Glu111Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;D;D;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.6	.;H;H;H
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.9	.;D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.97
MutPred		0.90		.;Loss of catalytic residue at E111 (P = 0.0741);Loss of catalytic residue at E111 (P = 0.0741);Loss of catalytic residue at E111 (P = 0.0741);
MVP		0.91
MPC		0.83
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.95
gMVP		0.92

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: rs1554186385; hg19: chr6-42146148;