rs1554707637

Variant names:

• chr9-99218129-GG-TCA
• rs1554707637
• NM_033087.4:c.1055_1056delCCinsTGA

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_033087.4(ALG2):​c.1055_1056delCCinsTGA​(p.Ser352LeufsTer3) variant causes a frameshift, stop gained change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S352S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALG2 NM_033087.4 frameshift, stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 7.17
• Publications: 0 publications found

Genes affected

ALG2 (HGNC:23159): (ALG2 alpha-1,3/1,6-mannosyltransferase) This gene encodes a member of the glycosyltransferase 1 family. The encoded protein acts as an alpha 1,3 mannosyltransferase, mannosylating Man(2)GlcNAc(2)-dolichol diphosphate and Man(1)GlcNAc(2)-dolichol diphosphate to form Man(3)GlcNAc(2)-dolichol diphosphate. Defects in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ii). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2008]

ALG2 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 14

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• ALG2-congenital disorder of glycosylation

  Inheritance: Unknown, AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
• congenital myasthenic syndromes with glycosylation defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.157 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-99218129-GG-TCA is Pathogenic according to our data. Variant chr9-99218129-GG-TCA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 464893.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG2	NM_033087.4	c.1055_1056delCCinsTGA	p.Ser352LeufsTer3	frameshift_variant, stop_gained	Exon 2 of 2	ENST00000476832.2	NP_149078.1
ALG2	XM_047423996.1	c.776_777delCCinsTGA	p.Ser259LeufsTer3	frameshift_variant, stop_gained	Exon 2 of 2		XP_047279952.1
ALG2	NR_024532.2	n.1262_1263delCCinsTGA		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG2	ENST00000476832.2	c.1055_1056delCCinsTGA	p.Ser352LeufsTer3	frameshift_variant, stop_gained	Exon 2 of 2	1	NM_033087.4	ENSP00000417764.1
ALG2	ENST00000319033.7	c.776_777delCCinsTGA	p.Ser259LeufsTer3	frameshift_variant, stop_gained	Exon 2 of 2	1		ENSP00000326609.6
ALG2	ENST00000238477.5	n.*797_*798delCCinsTGA		non_coding_transcript_exon_variant	Exon 3 of 3	2		ENSP00000432675.2
ALG2	ENST00000238477.5	n.*797_*798delCCinsTGA		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000432675.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

ALG2-congenital disorder of glycosylation Pathogenic:1

Nov 22, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Predicted Consequence/Location: Inframe deletion located in a nonrepeat region - predicted to change the length of the protein and disrupt normal protein function. The variant has been reported to be associated with ALG2-related disorder (VCV000464893). Therefore, the variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not specified Uncertain:1

Feb 07, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALG2 c.1055_1056delinsTGA (p.Ser352LeufsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein in the Glycosyl transferase, family 1 domain (IPR001296). Although this truncation is not predicted to cause absense of the protein through nonsense mediated decay, and truncations downstream of this position have been classified as uncertain significance in ClinVar (1053713), the variant may potentially alter protein function by altering the last 65 amino acids in the protein sequence. The variant was absent in 281616 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1055_1056delinsTGA in individuals affected with Congenital Disorder Of Glycosylation, Type 1i and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS. -

Inborn genetic diseases Uncertain:1

Mar 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not expected to trigger nonsense-mediated mRNA decay Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ALG2-congenital disorder of glycosylation;C4015597:Congenital myasthenic syndrome 14 Uncertain:1

Dec 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser352Leufs*3) in the ALG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 65 amino acid(s) of the ALG2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ALG2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2

Splicing

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

Other links and lift over

dbSNP: rs1554707637; hg19: chr9-101980411;