LARGE1 p.Thr364Thr

Variant names:

• chr22-33381957-G-G
• NM_133642.5:c.

Your query was ambiguous. Multiple possible variants found:

• chr22-33381958--
• chr22-33381958-G-A
• chr22-33381958-G-T
• chr22-33381958-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_133642.5(LARGE1):​c. variant causes a exon region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LARGE1 NM_133642.5 exon_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0640
• Publications: 0 publications found

Genes affected

LARGE1 (HGNC:6511): (LARGE xylosyl- and glucuronyltransferase 1) This gene encodes a member of the N-acetylglucosaminyltransferase gene family. It encodes a glycosyltransferase which participates in glycosylation of alpha-dystroglycan, and may carry out the synthesis of glycoprotein and glycosphingolipid sugar chains. It may also be involved in the addition of a repeated disaccharide unit. The protein encoded by this gene is the glycotransferase that adds the final xylose and glucuronic acid to alpha-dystroglycan and thereby allows alpha-dystroglycan to bind ligands including laminin 211 and neurexin. Mutations in this gene cause several forms of congenital muscular dystrophy characterized by cognitive disability and abnormal glycosylation of alpha-dystroglycan. Alternative splicing of this gene results in multiple transcript variants that encode the same protein. [provided by RefSeq, May 2018]

LARGE1 Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy-dystroglycanopathy type B6

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133642.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	NM_133642.5	MANE Select	c.		exon_region	Exon 9 of 15	NP_598397.1	O95461-1
	LARGE1	NM_001362949.2		c.		exon_region	Exon 10 of 16	NP_001349878.1	O95461-1
	LARGE1	NM_001362951.2		c.		exon_region	Exon 9 of 15	NP_001349880.1	O95461-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	ENST00000397394.8	TSL:5 MANE Select	c.		exon_region	Exon 9 of 15	ENSP00000380549.2	O95461-1
	LARGE1	ENST00000354992.7	TSL:1	c.		exon_region	Exon 10 of 16	ENSP00000347088.2	O95461-1
	LARGE1	ENST00000402320.6	TSL:1	c.		exon_region	Exon 9 of 14	ENSP00000385223.1	O95461-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.064

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr22-33777943;