rs1554308513

Variant names:

• chr6-146399414-A-G
• rs1554308513
• NM_001278064.2:c.2375A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001278064.2(GRM1):​c.2375A>G​(p.Tyr792Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRM1 NM_001278064.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3 U:2
• Conservation: PhyloP100: 9.32
• Publications: 2 publications found

Genes affected

GRM1 (HGNC:4593): (glutamate metabotropic receptor 1) This gene encodes a metabotropic glutamate receptor that functions by activating phospholipase C. 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 canonical alpha isoform of the encoded protein is a disulfide-linked homodimer whose activity is mediated by a G-protein-coupled phosphatidylinositol-calcium second messenger system. This gene may be associated with many disease states, including schizophrenia, bipolar disorder, depression, and breast cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

GRM1 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia 44

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal recessive spinocerebellar ataxia 13

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant 6-146399414-A-G is Pathogenic according to our data. Variant chr6-146399414-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438855.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278064.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM1	NM_001278064.2	MANE Select	c.2375A>G	p.Tyr792Cys	missense	Exon 7 of 8	NP_001264993.1
	GRM1	NM_001278067.1		c.2375A>G	p.Tyr792Cys	missense	Exon 7 of 8	NP_001264996.1
	GRM1	NM_001278065.2		c.2375A>G	p.Tyr792Cys	missense	Exon 8 of 10	NP_001264994.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM1	ENST00000282753.6	TSL:1 MANE Select	c.2375A>G	p.Tyr792Cys	missense	Exon 7 of 8	ENSP00000282753.1
	GRM1	ENST00000355289.8	TSL:1	c.2375A>G	p.Tyr792Cys	missense	Exon 7 of 8	ENSP00000347437.4
	GRM1	ENST00000492807.6	TSL:1	c.2375A>G	p.Tyr792Cys	missense	Exon 8 of 10	ENSP00000424095.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Dec 05, 2023

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified in at least one individual with autosomal dominant spinocerebellar ataxia. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 28886343)

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Spinocerebellar ataxia 44 Pathogenic:2

Jul 22, 2021

O&I group, Department of Genetics, University Medical Center of Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Nov 18, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.59		Gain of sheet (P = 0.1208)
MVP		0.95
MPC		1.9
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.94
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554308513; hg19: chr6-146720550; COSMIC: COSV51185896;