rs1200683561

Positions:

• chr17-38330861-G-GGT

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The ENST00000616987.5(GPR179):​c.2707_2708insAC​(p.Pro903HisfsTer67) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000269 in 1,449,354 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: GPR179 ENST00000616987.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.83

Genes affected

GPR179 (HGNC:31371): (G protein-coupled receptor 179) This gene encodes a member of the glutamate receptor subfamily of G protein-coupled receptors. The encoded protein has an EGF-like calcium binding domain and a seven transmembrane domain in the N-terminal region of the protein. Mutations in this gene are associated with congenital stationary night blindness type 1E. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.619 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-38330861-G-GGT is Pathogenic according to our data. Variant chr17-38330861-G-GGT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505393.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR179	NM_001004334.4	c.2707_2708insAC	p.Pro903HisfsTer67	frameshift_variant	11/11	ENST00000616987.5	NP_001004334.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR179	ENST00000616987.5	c.2707_2708insAC	p.Pro903HisfsTer67	frameshift_variant	11/11	1	NM_001004334.4	ENSP00000483469	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000269 AC: 39 AN: 1449354 Hom.: 0 Cov.: 36 AF XY: 0.0000236 AC XY: 17 AN XY: 719940

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: 0.0000298

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital stationary night blindness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 24, 2017

The p.Pro903HisfsX67 (NM_001004334.2 c.2706_2707dupAC) variant in GPR179 has not been previously reported in individuals with congenital stationary night blindn ess and was absent from large population studies. This variant is predicted to c ause a frameshift, which alters the protein?s amino acid sequence beginning at p osition 903 and leads to a premature termination codon 67 amino acids downstream . This alteration is then predicted to lead to a truncated or absent protein. Bi allelic loss of function of the GPR179 gene has been associated with congenital stationary night blindness. In summary, although additional studies are require d to fully establish a null effect on the protein, the p.Pro903HisfsX67 variant is likely pathogenic for congenital stationary night blindness in an autosomal r ecessive manner based upon its predicted functional impact. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 21, 2023

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 505393). This variant has not been reported in the literature in individuals affected with GPR179-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro903Hisfs*67) in the GPR179 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1465 amino acid(s) of the GPR179 protein. -

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: rs1200683561; hg19: chr17-36486744;