Variant: NM_001164508.2(NEB):c.1493A>G (p.Asp498Gly)

CA348825220

533979 (ClinVar)

Gene: NEB

Condition: nemaline myopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 79266f92-7df8-40de-be2e-c648de9e1355

Approved on: 2025-03-10

Published on: 2025-03-27

HGVS expressions

NM_001164508.2:c.1493A>G
NM_001164508.2(NEB):c.1493A>G (p.Asp498Gly)
NC_000002.12:g.151696713T>C
CM000664.2:g.151696713T>C
NC_000002.11:g.152553227T>C
CM000664.1:g.152553227T>C
NC_000002.10:g.152261473T>C
NG_009382.2:g.42775A>G
ENST00000397345.8:c.1493A>G
ENST00000427231.7:c.1493A>G
ENST00000172853.14:c.1493A>G
ENST00000397345.7:c.1493A>G
ENST00000409198.5:c.1493A>G
ENST00000427231.6:c.1493A>G
ENST00000489048.1:n.392A>G
ENST00000603639.5:c.1493A>G
ENST00000604864.5:c.1493A>G
ENST00000618972.4:c.1493A>G
NM_001164507.1:c.1493A>G
NM_001164508.1:c.1493A>G
NM_001271208.1:c.1493A>G
NM_004543.4:c.1493A>G
NM_001271208.2:c.1493A>G
NM_004543.5:c.1493A>G
NM_001164507.2:c.1493A>G

Likely Pathogenic

• Met criteria codes: PM3_Strong PP4 PM2_Supporting

• Not Met criteria codes: PS2 PS4 PS3 PS1 BP5 BP7 BP2 BP4 BP1 BP3 PP1 PP3 PP2 PM1 PM5 PM4 PM6 BA1 BS2 BS4 BS3 BS1 PVS1

Expert Panel

Congenital Myopathies VCEP

Criteria Specification Information

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

Evidence submitted by expert panel

Congenital Myopathies VCEP

The NM_001164508.2 c.1493A>G (p.Asp498Gly) variant in NEB is a missense variant predicted to cause a substitution of aspartic acid by glycine at amino acid 498. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00005120 (1/19532) alleles) in East Asian population, which is lower than the ClinGen Congenital Myopathies VCEP threshold (≤0.0000559) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has previously been observed in probands who have had nemaline bodies on muscle biopsy (PMID:32403337; Invitae internal data SCV000659742.9) (PP4). The variant has previously been reported in trans with pathogenic variants or rare variants of uncertain significance in 4 probands with clinical features of congenital myopathy (PMID: 33333461; Synnovis internal data SCV001468505.1; Invitae internal data SCV000659742.9) (PM3_Strong). In summary, this variant meets the criteria to be classified as likely pathogenic for Nemaline Myopathy for autosomal recessive inheritance based on the ACMG/AMP criteria applied as specified by the ClinGen Congenital Myopathy VCEP: (PM3_Strong, PP4, PM2_Supporting; ClinGen Congenital Myopathies VCEP Specifications version 1.0.0; 3/10/2025).

Met criteria codes

• PM3_Strong: PMID: 33333461 observed a case where a patient was found to have this variant with the NM_001271208.1(NEB):c.21076C>T p.Arg7026* variant (ClinVar: Pathogenic/Likely Pathogenic). The same proband may also be observed in PMID: 32403337 where both variants were found along with a similar phenotype and the papers have similar authors. Internal data also found the variant in a homozygous state for a proband. Invitae reported 3 internal patients with nemaline myopathy and muscle weakness who had the variant with a second pathogenic NEB variant.
• PP4: In PMID:32403337, the patient observed with the variant was noted to have nemaline bodies on muscle biopsy.
• PM2_Supporting: The variant has a minor allele frequency of 0.00001, which is less than the 0.0000559 threshold set for NEB

Not Met criteria codes

• PS2: No segregation data is available
• PS4: No case-control studies were found and NEB is a recessive gene so PS4 cannot be applied
• PS3: Experimental studies were not performed
• PS1: No other variants are identified in the same codon
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: This variant is a missense variant
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: The REVEL score is 0.182, which is above the 0.15 threshold
• BP1: Both missense and truncating variants can be pathogenic in NEB and therefore BP1 cannot be applied
• BP3: This variant is a missense variant
• PP1: No segregation data available
• PP3: The REVEL score is 0.182, which is below the 0.7 threshold
• PP2: PP2 does not apply to NEB because missense variants are not constrained.
• PM1: There are no hot spots or critical domains in NEB at this time
• PM5: No other variants are identified in the same codon
• PM4: This variant is a missense variant
• PM6: No segregation data is available
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: This variant was not observed in a homozygous healthy adult
• BS4: No segregation data available
• BS3: Experimental studies were not performed
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: This is a missense variant