NM_133642.5:c.992C>T

Variant names:

• chr22-33384205-G-A
• rs267607210
• NM_133642.5:c.992C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_133642.5(LARGE1):​c.992C>T​(p.Ser331Phe) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S331S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LARGE1 NM_133642.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.45
• Publications: 6 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 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797
• PP5: Variant 22-33384205-G-A is Pathogenic according to our data. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-33384205-G-A is described in CliVar as Pathogenic. Clinvar id is 6221.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARGE1	NM_133642.5	c.992C>T	p.Ser331Phe	missense_variant	Exon 8 of 15	ENST00000397394.8	NP_598397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000397394.8	c.992C>T	p.Ser331Phe	missense_variant	Exon 8 of 15	5	NM_133642.5	ENSP00000380549.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 Pathogenic:1

Nov 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;.;.;D;D;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D
MetaSVM	Benign	-0.63	T
PhyloP100		9.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.5	.;.;.;D;D;D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0020	.;.;.;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D
Polyphen		0.88, 0.93	.;.;.;P;P;P;.
Vest4		0.97, 0.97, 0.98
MutPred		0.54		.;.;.;Loss of disorder (P = 0.0428);Loss of disorder (P = 0.0428);Loss of disorder (P = 0.0428);.;
MVP		0.24
MPC		1.5
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.59
gMVP		0.92
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: rs267607210; hg19: chr22-33780191; COSMIC: COSV61673193;