rs62638197

chr5-178994808-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000843.4(GRM6):c.137C>T(p.Pro46Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,280,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P46P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000094 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: GRM6 NM_000843.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.35

Genes affected

GRM6 (HGNC:4598): (glutamate metabotropic receptor 6) L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. Mutations in this gene result in congenital stationary night blindness type 1B. [provided by RefSeq, May 2018]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 5-178994808-G-A is Pathogenic according to our data. Variant chr5-178994808-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-178994808-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM6	NM_000843.4	c.137C>T	p.Pro46Leu	missense_variant	2/11	ENST00000517717.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM6	ENST00000517717.3	c.137C>T	p.Pro46Leu	missense_variant	2/11	5	NM_000843.4	P1
GRM6	ENST00000231188.9	c.137C>T	p.Pro46Leu	missense_variant	1/10	2		P1
GRM6	ENST00000650031.1	c.137C>T	p.Pro46Leu	missense_variant	3/12			P1

Frequencies

GnomAD3 genomes AF: 0.0000937 AC: 14 AN: 149464 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000730

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000164

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000162 AC: 183 AN: 1130906 Hom.: 0 Cov.: 32 AF XY: 0.000158 AC XY: 87 AN XY: 549874

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: 0.000187

Gnomad4 OTH exome AF: 0.000135

GnomAD4 genome AF: 0.0000936 AC: 14 AN: 149572 Hom.: 0 Cov.: 33 AF XY: 0.0000959 AC XY: 7 AN XY: 72994

Gnomad4 AFR AF: 0.0000727

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000164

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000680

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2017	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 30, 2023	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. -
not provided, no classification provided	literature only	Retina International	-	- -

Congenital stationary night blindness 1B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2005

- -

Congenital stationary night blindness Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;.;.
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.3	M;M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-8.0	D;D;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		0.95	P;P;P
Vest4		0.90
MutPred		0.86		Gain of catalytic residue at P46 (P = 0.0246);Gain of catalytic residue at P46 (P = 0.0246);Gain of catalytic residue at P46 (P = 0.0246);
MVP		0.86
MPC		2.3
ClinPred		0.96	D
GERP RS		3.2
Varity_R		0.52
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs62638197; hg19: chr5-178421809;