Submissions for variant NM_001004334.4(GPR179):c.984del (p.Ser329fs)

dbSNP: rs770066665

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000309713	SCV000329996	pathogenic	not provided	2022-06-13	criteria provided, single submitter	clinical testing	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)
Illumina Laboratory Services, Illumina	RCV000024203	SCV000402523	uncertain significance	Congenital stationary night blindness 1E	2019-04-08	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000505034	SCV000967791	pathogenic	Congenital stationary night blindness	2016-11-10	criteria provided, single submitter	clinical testing	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.
Blueprint Genetics	RCV001073427	SCV001238968	pathogenic	Retinal dystrophy	2019-02-01	criteria provided, single submitter	clinical testing
Invitae	RCV000309713	SCV001592171	pathogenic	not provided	2023-12-23	criteria provided, single submitter	clinical testing	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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000309713	SCV001762090	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000024203	SCV002767357	pathogenic	Congenital stationary night blindness 1E	2021-05-06	criteria provided, single submitter	clinical testing	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
Institute of Human Genetics, University of Leipzig Medical Center	RCV000024203	SCV004027725	pathogenic	Congenital stationary night blindness 1E	2023-07-26	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4_MOD,PM2_SUP
OMIM	RCV000024203	SCV000045494	pathogenic	Congenital stationary night blindness 1E	2012-02-10	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505034	SCV000598885	pathogenic	Congenital stationary night blindness	2015-01-01	no assertion criteria provided	research