Variant: NM_001005361.3(DNM2):c.1102G>A (p.Glu368Lys)

CA118661

7282 (ClinVar)

Gene: DNM2

Condition: centronuclear myopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: f50ef19f-b4a3-4934-9f09-07949b4c0cc2

Approved on: 2024-10-25

Published on: 2025-03-17

HGVS expressions

NM_001005361.3:c.1102G>A
NM_001005361.3(DNM2):c.1102G>A (p.Glu368Lys)
NC_000019.10:g.10793829G>A
CM000681.2:g.10793829G>A
NC_000019.9:g.10904505G>A
CM000681.1:g.10904505G>A
NC_000019.8:g.10765505G>A
NG_008792.1:g.80751G>A
ENST00000682285.1:n.1290G>A
ENST00000682524.1:n.1290G>A
ENST00000683738.1:n.1290G>A
ENST00000355667.11:c.1102G>A
ENST00000389253.9:c.1102G>A
ENST00000355667.10:c.1102G>A
ENST00000359692.10:c.1102G>A
ENST00000389253.8:c.1102G>A
ENST00000408974.8:c.1102G>A
ENST00000585892.5:c.1102G>A
ENST00000587830.2:c.358G>A
ENST00000591701.5:n.462G>A
NM_001005360.2:c.1102G>A
NM_001005361.2:c.1102G>A
NM_001005362.2:c.1102G>A
NM_001190716.1:c.1102G>A
NM_004945.3:c.1102G>A
NM_001190716.2:c.1102G>A
NM_001005360.3:c.1102G>A
NM_001005362.3:c.1102G>A
NM_004945.4:c.1102G>A

Pathogenic

• Met criteria codes: PS3_Moderate PM2_Supporting PS4 PP3 PP2 PS2_Very Strong

• Not Met criteria codes: BA1 BS1

Expert Panel

Congenital Myopathies VCEP

Criteria Specification Information

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

Evidence submitted by expert panel

Congenital Myopathies VCEP

The NM_001005361.3:c.1102G>A variant in DNM2 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 368 (p.Glu368Lys). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.799, 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 at least 6 probands with centronuclear myopathy (PS4; PMIDs: 16227997, 22613877, 25501959, 27159402, 33124102). Of those 6 individuals, the variant was identified as a de novo occurrence with confirmed parental relationships in at least 3 of those individuals with centronuclear myopathy (PS2_VeryStrong; PMIDs: 16227997, 27159402, 33124102). Oligomerization in Sf9 cells showed defective autoinhibition of self-assembly, indicating that this variant impacts protein function (PMID: 26199319). Additionally, GTPase activity in Sf9 cells was between 2–2.5-fold higher than wild-type DNM2 (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: PS2_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP2, PP3. (ClinGen Congenital Myopathies VCEP Specifications Version 1.0; 10/25/2024)

Met criteria codes

• PS3_Moderate: Oligomerization in Sf9 cells showed defective autoinhibition of self-assembly, indicating that this variant impacts protein function (PMID: 26199319). Additionally, GTPase activity in Sf9 cells was between 2–2.5-fold higher than wild-type DNM2 (PS3_Moderate).
• PM2_Supporting: This variant is absent from gnomAD v4.1 (PM2_Supporting).
• PS4: This variant has been reported in at least 6 probands with centronuclear myopathy (PS4; PMIDs: 16227997, 22613877, 25501959, 27159402, 33124102).
• PP3: The computational predictor REVEL gives a score of 0.799, which is above the threshold of 0.7, evidence that correlates with impact to DNM2 function (PP3).
• 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 (PP2).
• PS2_Very Strong: The variant was identified as a de novo occurrence with confirmed parental relationships in at least 3 individuals with centronuclear myopathy (PS2_VeryStrong; PMIDs: 16227997, 27159402, 33124102).

Not Met criteria codes

• 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