rs398123312

Variant names:

• chr16-8801827-TA-GC
• rs398123312
• NM_000303.3:c.95_96delTAinsGC

Variant summary

Our verdict is Pathogenic. The variant received 26 ACMG points: 26P and 0B. PS1_Very_Strong PS3 PM1 PM5 PP2 PP3 PP5_Very_Strong

The NM_000303.3(PMM2):​c.95_96delTAinsGC​(p.Leu32Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.00000805 in 2 alleles, including 0 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000696505: multiple functional studies show the variant to impede PMM2 wild type functions." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L32V) has been classified as Likely pathogenic.

• Frequency: GnomAD MNV: 𝑓 0.0000080 Genomes: not found (cov: 33)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.53
• Publications: 26 publications found

Genes affected

PMM2 (HGNC:9115): (phosphomannomutase 2) The protein encoded by this gene catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate, which is a precursor to GDP-mannose necessary for the synthesis of dolichol-P-oligosaccharides. Mutations in this gene have been shown to cause defects in glycoprotein biosynthesis, which manifests as carbohydrate-deficient glycoprotein syndrome type I. [provided by RefSeq, Jul 2008]

PMM2 Gene-Disease associations (from GenCC):

• congenital disorder of glycosylation type I

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• PMM2-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hyperinsulinemic hypoglycemia with polycystic kidney disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 26 ACMG points.

• PS1: Transcript NM_000303.3 (PMM2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000696505: multiple functional studies show the variant to impede PMM2 wild type functions.; SCV000944609: Experimental studies have shown that this missense change affects PMM2 function (PMID: 10922383, 11715002).; SCV005388937: Published functional studies demonstrate a damaging effect with significantly reduced phosphomannomutase 2 enzyme activity compared to wild-type (PMID: 10922383, 11715002, 21541725); SCV003555620: In E. coli and S. cerevisiae, this mutation demonstrated reduced PMM activity of approximately 40-45% of wild type levels (Vuillaumier-Barrot, 2000; Westphal, 2001; Vega, 2011); SCV005356984: Functional studies showed that the p.Leu32Arg variant results in reduced enzyme activities (Westphal et al. 2001. PubMed ID: 11715002).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000303.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-8801826-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1945008.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 89 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: -1.3872 (below the threshold of 3.09). Trascript score misZ: -1.8083 (below the threshold of 3.09). GenCC associations: The gene is linked to PMM2-congenital disorder of glycosylation, congenital disorder of glycosylation type I, hyperinsulinemic hypoglycemia with polycystic kidney disease.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 16-8801827-TA-GC is Pathogenic according to our data. Variant chr16-8801827-TA-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 92807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000303.3. 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
	PMM2	NM_000303.3	MANE Select	c.95_96delTAinsGC	p.Leu32Arg	missense	N/A	NP_000294.1	A0A0S2Z4J6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM2	ENST00000268261.9	TSL:1 MANE Select	c.95_96delTAinsGC	p.Leu32Arg	missense	N/A	ENSP00000268261.4	O15305-1
	PMM2	ENST00000565221.5	TSL:1	n.95_96delTAinsGC		non_coding_transcript_exon	Exon 2 of 6	ENSP00000457932.1	H3BV34
	PMM2	ENST00000566540.5	TSL:1	n.95_96delTAinsGC		non_coding_transcript_exon	Exon 2 of 6	ENSP00000454284.1	H3BM92

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

GnomAD MNV AF: 0.00000805 AC: 2 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	PMM2-congenital disorder of glycosylation (3)
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	PMM2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=170/130	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs398123312; hg19: chr16-8895684;