chr6-42178809-GC-TT

Position:

• chr6-42178809-GC-TT

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_Very_Strong PM2 PP3 PP5_Moderate

The NM_001384910.1(GUCA1A):​c.359_360delinsTT​(p.Arg120Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R120H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GUCA1A NM_001384910.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.70

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:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS1: Transcript NM_001384910.1 (GUCA1A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 802212
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 6-42178809-GC-TT is Pathogenic according to our data. Variant chr6-42178809-GC-TT is described in ClinVar as [Pathogenic]. Clinvar id is 453246.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUCA1A	NM_001384910.1	c.359_360delinsTT	p.Arg120Leu	missense_variant	3/4	ENST00000372958.2
GUCA1ANB-GUCA1A	NM_001319061.2	c.359_360delinsTT	p.Arg120Leu	missense_variant	5/6
GUCA1ANB-GUCA1A	NM_000409.5	c.359_360delinsTT	p.Arg120Leu	missense_variant	5/6
GUCA1ANB-GUCA1A	NM_001319062.2	c.359_360delinsTT	p.Arg120Leu	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCA1A	ENST00000372958.2	c.359_360delinsTT	p.Arg120Leu	missense_variant	3/4	1	NM_001384910.1	P1
GUCA1A	ENST00000679182.1	c.140_141delinsTT	p.Arg47Leu	missense_variant	2/3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cone dystrophy 3 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 15, 2017	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Jun 05, 2020	This variant is interpreted as pathogenic for Cone dystrophy 3, 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); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1 upgraded to strong); Well-established functional studies show a deleterious effect (PS3). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554186441; hg19: chr6-42146547;