Submissions for variant NM_000843.4(GRM6):c.137C>T (p.Pro46Leu)

gnomAD frequency: 0.00009  dbSNP: rs62638197

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000086025	SCV000582705	likely pathogenic	not provided	2017-12-05	criteria provided, single submitter	clinical testing	The P46L variant in the GRM6 gene has been reported previously in trans with another GRM6 variant in an individual with congenital stationary night blindness (Zeitz et al., 2005). The P46L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The P46L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Functional studies of the P46L variant demonstrated a transport defect with intracellular retention of the receptor (Zeitz et al., 2007; Beqollari et al., 2009). We interpret P46L as a likely pathogenic variant.
Invitae	RCV000086025	SCV001401018	likely pathogenic	not provided	2023-08-30	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects GRM6 function (PMID: 17405131, 19666700). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GRM6 protein function. ClinVar contains an entry for this variant (Variation ID: 5844). This missense change has been observed in individual(s) with congenital stationary night blindness (PMID: 16249515, 28041643, 32531858). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 46 of the GRM6 protein (p.Pro46Leu). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM	RCV000006201	SCV000026383	pathogenic	Congenital stationary night blindness 1B	2005-11-01	no assertion criteria provided	literature only
Retina International	RCV000086025	SCV000118168	not provided	not provided		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504939	SCV000598707	likely pathogenic	Congenital stationary night blindness	2015-01-01	no assertion criteria provided	research