rs151173406

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_019109.5(ALG1):c.826C>T(p.Arg276Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,611,786 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R276Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ALG1
NM_019109.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.77

Variant links:

Genes affected

ALG1 (HGNC:18294): (ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase) The enzyme encoded by this gene catalyzes the first mannosylation step in the biosynthesis of lipid-linked oligosaccharides. This gene is mutated in congenital disorder of glycosylation type Ik. [provided by RefSeq, Dec 2008]

ALG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 16-5078842-C-T is Pathogenic according to our data. Variant chr16-5078842-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-5078842-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ALG1	NM_019109.5 linkuse as main transcript	c.826C>T	p.Arg276Trp	missense_variant	7/13	ENST00000262374.10
ALG1	NM_001330504.2 linkuse as main transcript	c.493C>T	p.Arg165Trp	missense_variant	7/13
ALG1	XM_017023457.3 linkuse as main transcript	c.826C>T	p.Arg276Trp	missense_variant	7/12
ALG1	XR_007064892.1 linkuse as main transcript	n.833C>T		non_coding_transcript_exon_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG1	ENST00000262374.10 linkuse as main transcript	c.826C>T	p.Arg276Trp	missense_variant	7/13	1	NM_019109.5	P1	Q9BT22-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000804

AC:

AN:

248830

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135056

show subpopulations

Gnomad AFR exome

AF:

0.0000640

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1459606

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ALG1-congenital disorder of glycosylation

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 17, 2023	ClinVar contains an entry for this variant (Variation ID: 30539). 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 ALG1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with congenital disorder of glycosylation (PMID: 20679665, 26931382; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 276 of the ALG1 protein (p.Arg276Trp). This variant is present in population databases (rs151173406, gnomAD 0.003%). -
Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	May 07, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 12, 2023	Variant summary: ALG1 c.826C>T (p.Arg276Trp) results in a non-conservative amino acid change located in the glycosyl transferase, family 1 domain (IPR001296) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248830 control chromosomes (gnomAD). c.826C>T has been reported as a compound heterozygous genotype in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1K, including at least one individual where it was confirmed to be in trans with a pathogenic variant and one case where it was reported as a de novo occurrence (e.g. Dupre_2010, Ng_2016, Fang_2021, Abu Bakar_2022). These data indicate that the variant is very likely to be associated with disease. A functional study examining the impact of the variant using an alg1-deficient yeast strain found that the variant was not able to rescue the growth-deficient phenotype to the same extent as the wild type protein (Ng_2016), however, as this assay is not quantitative it does not necessarily allow strong conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 35279850, 20679665, 34020146, 26931382). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is in trans with the other pathogenic variant. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.66; 3Cnet: 0.55). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030539). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Congenital disorder of glycosylation

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

May 25, 2017

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 11, 2020

The variant impaired the normal function of ALG1 (Ng et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26931382, 20679665, 27670784) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.25

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.93

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Uncertain

0.26

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.51

Sift4G

Uncertain

0.014

D;D;D;D

Polyphen

0.96

.;D;.;.

Vest4

0.92

MVP

0.95

MPC

0.22

ClinPred

0.99

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.80

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.80

Position offset: -6

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over