rs1200683561

Variant names:

• chr17-38330861-G-GGT
• rs1200683561
• NM_001004334.4:c.2706_2707dupAC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_001004334.4(GPR179):​c.2706_2707dupAC​(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 NM_001004334.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.83
• Publications: 0 publications found

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]

GPR179 Gene-Disease associations (from GenCC):

• congenital stationary night blindness 1E

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• GPR179-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 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. There are 8 pathogenic variants in the truncated region.
• 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 VariationId is 505393.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR179	NM_001004334.4	c.2706_2707dupAC	p.Pro903HisfsTer67	frameshift_variant	Exon 11 of 11	ENST00000616987.5	NP_001004334.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR179	ENST00000616987.5	c.2706_2707dupAC	p.Pro903HisfsTer67	frameshift_variant	Exon 11 of 11	1	NM_001004334.4	ENSP00000483469.2

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

African (AFR) AF: 0.00 AC: 0 AN: 33314

American (AMR) AF: 0.00 AC: 0 AN: 42628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25780

East Asian (EAS) AF: 0.00 AC: 0 AN: 39278

South Asian (SAS) AF: 0.00 AC: 0 AN: 84306

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.0000298 AC: 33 AN: 1106368

Other (OTH) AF: 0.000100 AC: 6 AN: 59864

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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

Jan 24, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GPR179-related conditions. ClinVar contains an entry for this variant (Variation ID: 505393). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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
PhyloP100		2.8
Mutation Taster		=125/75	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1200683561; hg19: chr17-36486744;