rs770066665

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001004334.4(GPR179):c.984del(p.Ser329LeufsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 1,611,632 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

GPR179
NM_001004334.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:1

Conservation

PhyloP100: 0.463

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-38337639-AG-A is Pathogenic according to our data. Variant chr17-38337639-AG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 31204.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=7, Uncertain_significance=1}. Variant chr17-38337639-AG-A is described in Lovd as [Likely_pathogenic]. Variant chr17-38337639-AG-A is described in Lovd as [Pathogenic]. Variant chr17-38337639-AG-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR179	NM_001004334.4 linkuse as main transcript	c.984del	p.Ser329LeufsTer4	frameshift_variant	3/11	ENST00000616987.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR179	ENST00000616987.5 linkuse as main transcript	c.984del	p.Ser329LeufsTer4	frameshift_variant	3/11	1	NM_001004334.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000466

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000808

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000508

AC:

126

AN:

248208

Hom.:

AF XY:

0.000557

AC XY:

AN XY:

134738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00340

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000557

Gnomad NFE exome

AF:

0.000691

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000337

AC:

492

AN:

1459406

Hom.:

Cov.:

AF XY:

0.000368

AC XY:

267

AN XY:

726000

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000227

Gnomad4 ASJ exome

AF:

0.00219

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000712

Gnomad4 NFE exome

AF:

0.000338

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000466

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.000808

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00126

Hom.:

Bravo

AF:

0.000404

EpiCase

AF:

0.000709

EpiControl

AF:

0.000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital stationary night blindness 1E

Pathogenic:3Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 08, 2019	The GPR179 c.984delC (p.Ser329LeufsTer4) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Ser329LeufsTer4 variant has been reported in two studies in which it is found in a compound heterozygous state, one with a frameshift variant and the other two with a missense variant as the second allele in three individuals affected with an autosomal recessive form of congenital stationary night blindness (Audo et al. 2012; Peachey et al. 2012). The p.Ser329LeufsTer4 variant was absent from 582 control chromosomes (Audo et al. 2012; Peachey et al. 2012) but is reported at a frequency of 0.00607 in the European American population of the Exome Sequencing Project and found in a homozygous state in one individual in the Genome Aggregation Database. The information about this variant is limited. Therefore, the p.Ser329LeufsTer4 variant is classified as a variant of uncertain significance, but suspicious for pathogenicity, for an autosomal recessive form of congenital stationary night blindness. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 10, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive complete congenital stationary night blindness, type 1E (MIM#614565). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (150 heterozygotes, 1 homozygote). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many other loss of function variants have previously been classified as pathogenic in individuals with night blindness (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as in multiple individuals with autosomal recessive complete congenital stationary night blindness (ClinVar, PMID: 22325361, PMID: 22325362). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 26, 2023	Criteria applied: PVS1,PS4_MOD,PM2_SUP -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2022	Reported previously in the homozygous state and in the compound heterozygous state with another GPR179 variant, in association with congenital stationary night blindness (Peachey et al., 2012; Audo et al., 2012; Carss et al., 2017); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30609409, 30487145, 22325361, 28041643, 31980526, 32581362, 31589614, 27535533, 22325362) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 23, 2023	This sequence change creates a premature translational stop signal (p.Ser329Leufs*4) in the GPR179 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GPR179 are known to be pathogenic (PMID: 22325361, 22325362). This variant is present in population databases (rs770066665, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with congenital stationary night blindness (PMID: 22325361). ClinVar contains an entry for this variant (Variation ID: 31204). For these reasons, this variant has been classified as Pathogenic. -

Congenital stationary night blindness

Pathogenic:2

Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 10, 2016	The p.Ser329LeufsX4 variant in GPR179 has been reported three individuals with c omplete congenital stationary night blindness in the compound heterozygous state (Audo 2012, Peachey 2012). This variant has also been identified in 61/120,604 of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs770066665). This p.Ser329LeufsX4 variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at posit ion 329 and leads to a premature termination codon 4 amino acids downstream. Thi s alteration is then predicted to lead to a truncated or absent protein. In summ ary, this variant meets criteria to be classified as pathogenic for congenital s tationary night blindness in an autosomal recessive manner based upon case obser vations, low frequency in controls, and a predicted null effect on protein funct ion. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over