6-42178410-A-T

Variant names:

• chr6-42178410-A-T
• rs1554186385
• NM_001384910.1:c.332A>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 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
• Publications: 3 publications found

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]

GUCA1ANB-GUCA1A (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

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001384910.1
• 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 ClinVar as Likely_pathogenic. ClinVar VariationId is 438157.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 21 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Trascript score misZ: 0.22619 (below the threshold of 3.09). GenCC associations: The gene is linked to cone dystrophy 3, cone-rod dystrophy 14, hereditary macular dystrophy, cone dystrophy, central areolar choroidal dystrophy, cone-rod dystrophy.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 962836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCA1A	ENST00000372958.2	c.332A>T	p.Glu111Val	missense_variant	Exon 2 of 4	1	NM_001384910.1	ENSP00000362049.1
GUCA1ANB-GUCA1A	ENST00000654459.1	c.332A>T	p.Glu111Val	missense_variant	Exon 3 of 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

Jun 05, 2020

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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

Feb 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. For these reasons, this variant has been classified as Pathogenic. 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 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. 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
PhyloP100		9.3
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
PromoterAI		-0.031	Neutral
Varity_R		0.95
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554186385; hg19: chr6-42146148;