rs80338709

Variant names:

• chr16-8847806-G-C
• rs80338709
• NM_000303.3:c.722G>C
• PMM2 p.Cys241Ser

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 15 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2_SupportingPM5PP3_ModeratePP5_Strong

The NM_000303.3(PMM2):c.722G>C (p.Cys241Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000645 (AC=104) in the gnomAD database across 1,613,056 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000582. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.25). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000633728: Experimental studies have shown that this missense change affects PMM2 function (PMID:11715002, 21541725, 22012410, 26014514)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.C241R: Likely_pathogenic (ClinVar VariationId 2847057, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23 O:1
• Conservation: PhyloP100: 8.25
• Publications: 40 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: G2P, Labcorp Genetics (formerly Invitae), Natera, PanelApp Australia, Orphanet, ClinGen
• hyperinsulinemic hypoglycemia with polycystic kidney disease

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, ClinGen

ENSG00000260350 (HGNC:58482):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 15 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000633728: Experimental studies have shown that this missense change affects PMM2 function (PMID: 11715002, 21541725, 22012410, 26014514).; SCV000696504: "Patient fibroblasts (which also carry a second pathogenic variant) show ~30% residual enzyme activity, and functional studies using expression systems also show <30% residual enzyme activity."; SCV004024507: Experimental studies have demonstrated that this amino acid substitution affects folding of the PMM2 protein, leading to abnormal protein aggregation and reduced PMM2 activity.; SCV006582743: Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 11715002, 21541725).; SCV002067359: Functional analyses have demonstrated that the p.Cys241Ser change affects folding of the PMM2 protein, leading to abnormal protein aggregation and intermediate residual PMM2 activity (PMIDs 26014514, 21541725).; SCV002072677: Published functional studies demonstrate C241S reduced enzyme activity and affected folding properties of the PMM2 protein (PMID: 26014514)
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 8 pathogenic, 1 benign (OR vs. background: 28.3).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000582 — borderline rare for AR gene (base 0.001, raised to 0.0049 by highest known P/LP ClinVar AF 0.0049) — PM2 supporting.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.C241R: Likely_pathogenic (ClinVar VariationId 2847057, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (23/23 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000303.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM2	NM_000303.3	MANE Select	c.722G>C	p.Cys241Ser	missense	Exon 8 of 8	NP_000294.1	O15305-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM2	ENST00000268261.9	TSL:1 MANE Select	c.722G>C	p.Cys241Ser	missense	Exon 8 of 8	ENSP00000268261.4	O15305-1
	PMM2	ENST00000565221.5	TSL:1	n.*340G>C		3_prime_UTR	Exon 6 of 6	ENSP00000457932.1	H3BV34
	PMM2	ENST00000566540.5	TSL:1	n.*344G>C		3_prime_UTR	Exon 6 of 6	ENSP00000454284.1	H3BM92

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000243	AC:37	Hom:0	AN:152224	Cov:33
GnomAD2 exomes	AF: 0.0000598	AC:15	Hom:	AN:250796	Cov:
GnomAD4 exome	AF: 0.0000459	AC:67	Hom:0	AN:1460832	Cov:30
GnomAD4 genome	AF: 0.000243	AC:37	Hom:0	AN:152224	Cov:33
TOPMed (Bravo)	AF: 0.000212	AC:56	Hom:1	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000279	AC:8	Hom:0	AN:28638	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.00	0	28844
Epi25(Epilepsy)	0.0000477	2	41958	0.000105	7	66878
SCHEMA(Schizophrenia)	0.0000798	9	112744	0.0000474	9	190044

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	PMM2-congenital disorder of glycosylation (13)
9	-	-	not provided (9)
1	-	-	Inborn genetic diseases (1)
1	-	-	PMM2-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
GPN-Star LLR	N/A	-5.6
GPN-Star score	N/A	5.6
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	3/97	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.1	M
PhyloP100	Pathogenic	8.3
popEVE	Benign	-3.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.0	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Pathogenic	0.93
Sift	Benign	0.042	D
Sift4G	Benign	0.21	T
Varity_R	N/A	0.94
VESM-3B	Benign	-8.8

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

dbSNP: rs80338709;

hg19: chr16-8941663;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar