The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_001005361.3(DNM2):c.1852G>A (p.Ala618Thr)

CA404041079

449326 (ClinVar)

Gene: DNM2
Condition: centronuclear myopathy
Inheritance Mode: Autosomal dominant inheritance
UUID: aa115c72-331e-4f61-9a5b-aa1abd9bb9e7
Approved on: 2024-08-07
Published on: 2024-10-01

HGVS expressions

NM_001005361.3:c.1852G>A
NM_001005361.3(DNM2):c.1852G>A (p.Ala618Thr)
NC_000019.10:g.10823858G>A
CM000681.2:g.10823858G>A
NC_000019.9:g.10934534G>A
CM000681.1:g.10934534G>A
NC_000019.8:g.10795534G>A
NG_008792.1:g.110780G>A
ENST00000681972.1:n.1283G>A
ENST00000355667.11:c.1852G>A
ENST00000389253.9:c.1852G>A
ENST00000355667.10:c.1852G>A
ENST00000359692.10:c.1840G>A
ENST00000389253.8:c.1852G>A
ENST00000408974.8:c.1840G>A
ENST00000585892.5:c.1852G>A
ENST00000590787.1:n.3351G>A
ENST00000590806.5:n.4040G>A
ENST00000593203.1:n.635G>A
NM_001005360.2:c.1852G>A
NM_001005361.2:c.1852G>A
NM_001005362.2:c.1840G>A
NM_001190716.1:c.1852G>A
NM_004945.3:c.1840G>A
NM_001190716.2:c.1852G>A
NM_001005360.3:c.1852G>A
NM_001005362.3:c.1840G>A
NM_004945.4:c.1840G>A
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Pathogenic

Met criteria codes 6
PM2_Supporting PS2 PS4 PP3 PP2 PS3_Moderate
Not Met criteria codes 3
BP4 BA1 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DNM2 Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Congenital Myopathies VCEP
The c.1852G>A (p.Ala618Thr) variant in DNM2 is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 618. This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.818, which is above the threshold of 0.7, evidence that correlates with impact to DNM2 function (PP3). DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported in four probands with features of centronuclear myopathy, two of which were de novo with parental relationships confirmed (PS4, PS2; PMIDs:17932957, 28357410, 34463354, 32154989). In vitro assays showed an increase in GTPase activity and oligomer stability indicating that this variant impacts protein function (PMIDs: 26199319, 20700106, 34744632)(PS3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PS2, PS3_Moderate, PM2_Supporting, PP2, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024).
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v4.1 (PM2_Supporting).
PS2
This variant has been reported as de novo observations with parental relationships confirmed in two probands with features of centronuclear myopathy (PS2; PMIDs:17932957, 32154989).
PS4
This variant has been reported in four probands with features of centronuclear myopathy, two of which were de novo with parental relationships confirmed (PS4, PS2; PMIDs:17932957, 28357410, 34463354, 32154989).
PP3
The computational predictor REVEL gives a score of 0.818, which is above the threshold of 0.7, evidence that correlates with impact to DNM2 function.
PP2
DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. The missense Z-score in gnomAD v2.1.1 is 3.48 which is above the threshold (3.09) set by the Congenital Myopathies VCEP.
PS3_Moderate
In vitro assays showed an increase in GTPase activity and oligomer stability indicating that this variant impacts protein function (PMIDs: 26199319, 20700106, 34744632)(PS3_M).
Not Met criteria codes
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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