chr17-15239575-G-A

Variant names:

• chr17-15239575-G-A
• rs104894621
• NM_000304.4:c.215C>T
• PMP22 p.Ser72Leu

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5PP3_ModeratePP5_Strong

The NM_000304.4(PMP22):c.215C>T (p.Ser72Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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: 9.82). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.S72P: Pathogenic (ClinVar VariationId 637384, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S72= (synonymous): Likely_benign (ClinVar VariationId 1186631, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMP22 NM_000304.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.82
• Publications: 24 publications found

Genes affected

PMP22 (HGNC:9118): (peripheral myelin protein 22) This gene encodes an integral membrane protein that is a major component of myelin in the peripheral nervous system. Studies suggest two alternately used promoters drive tissue-specific expression. Various mutations of this gene are causes of Charcot-Marie-Tooth disease Type IA, Dejerine-Sottas syndrome, and hereditary neuropathy with liability to pressure palsies. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

PMP22 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 1A

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hereditary neuropathy with liability to pressure palsies

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Orphanet
• Charcot-Marie-Tooth disease type 1E

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Charcot-Marie-Tooth disease type 3

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 46 pathogenic, 7 benign rare missense variants (OR vs. background: 31.0).; ±8 AA neighbourhood: 11 pathogenic, 0 benign (OR vs. background: 115.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	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.S72P: Pathogenic (ClinVar VariationId 637384, 1 star); Other variants at the same amino acid residue (not pathogenic): p.S72= (synonymous): Likely_benign (ClinVar VariationId 1186631, 2 stars)
	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 germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000304.4. 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
	PMP22 NM_000304.4	MANE Select	c.215C>T p.Ser72Leu	missense	Exon 4 of 5	Prot: NP_000295.1 UniProt:
	PMP22 NM_001281455.2		c.215C>T p.Ser72Leu	missense	Exon 4 of 5	Prot: NP_001268384.1 UniProt:
	PMP22 NM_001281456.2		c.215C>T p.Ser72Leu	missense	Exon 4 of 5	Prot: NP_001268385.1 UniProt:

PMP22 NM_000304.4

MANE Select

HGVSc / HGVSpc.215C>Tp.Ser72Leu

Exon rankExon 4 of 5

missense

Prot: NP_000295.1UniProt: Q01453Q6FH25

PMP22 NM_001281455.2

HGVSc / HGVSpc.215C>Tp.Ser72Leu

Exon rankExon 4 of 5

missense

Prot: NP_001268384.1UniProt: Q6FH25Q01453

PMP22 NM_001281456.2

HGVSc / HGVSpc.215C>Tp.Ser72Leu

Exon rankExon 4 of 5

missense

Prot: NP_001268385.1UniProt: Q01453Q6FH25

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PMP22 ENST00000312280.9	TSL:1MANE Select	c.215C>T p.Ser72Leu	missense	Exon 4 of 5	Prot: ENSP00000308937.3 UniProt:
	PMP22 ENST00000494511.7	TSL:1	c.11C>T p.Ser4Leu	missense	Exon 2 of 3	Prot: ENSP00000462782.2 UniProt:
	PMP22 ENST00000395938.7	TSL:1	c.204C>T p.Val68Val	synonymous	Exon 4 of 5	Prot: ENSP00000379269.3 UniProt:

PMP22 ENST00000312280.9

TSL:1MANE Select

HGVSc / HGVSpc.215C>Tp.Ser72Leu

Exon rankExon 4 of 5

missense

Prot: ENSP00000308937.3UniProt: Q01453

PMP22 ENST00000494511.7

TSL:1

HGVSc / HGVSpc.11C>Tp.Ser4Leu

Exon rankExon 2 of 3

missense

Prot: ENSP00000462782.2UniProt: J3KT36

PMP22 ENST00000395938.7

TSL:1

HGVSc / HGVSpc.204C>Tp.Val68Val

Exon rankExon 4 of 5

synonymous

Prot: ENSP00000379269.3UniProt: A0A6Q8PF08

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:23454	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Charcot-Marie-Tooth disease, type I (1)
1	-	-	Charcot-Marie-Tooth disease, type IA (1)
1	-	-	DEJERINE-SOTTAS SYNDROME, AUTOSOMAL DOMINANT (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	PMP22-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	1.0	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-7.3
GPN-Star score	N/A	7.3
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.92	D
Mutation Taster	N/A	1/99	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.2	M
PhyloP100	Pathogenic	9.8
popEVE	Benign	-4.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Varity_R	N/A	0.71
VESM-3B	Benign	-14

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs104894621;

hg19: chr17-15142892;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar