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_001164508.2(NEB):c.19097G>T (p.Ser6366Ile)

CA1907773

496132 (ClinVar)

Gene: NEB
Condition: nemaline myopathy
Inheritance Mode: Autosomal recessive inheritance
UUID: 0e36a3d1-723a-4b5b-ac30-0fabfeff6e8d
Approved on: 2024-08-07
Published on: 2024-10-01

HGVS expressions

NM_001164508.2:c.19097G>T
NM_001164508.2(NEB):c.19097G>T (p.Ser6366Ile)
NC_000002.12:g.151561212C>A
CM000664.2:g.151561212C>A
NC_000002.11:g.152417726C>A
CM000664.1:g.152417726C>A
NC_000002.10:g.152125972C>A
NG_009382.2:g.178276G>T
ENST00000690043.1:c.1948G>T
ENST00000397345.8:c.19097G>T
ENST00000427231.7:c.19097G>T
ENST00000172853.14:c.13994G>T
ENST00000397345.7:c.19097G>T
ENST00000409198.5:c.13994G>T
ENST00000413693.5:c.3287G>T
ENST00000427231.6:c.19097G>T
ENST00000603639.5:c.19097G>T
ENST00000604864.5:c.19097G>T
ENST00000618972.4:c.19097G>T
NM_001164507.1:c.19097G>T
NM_001164508.1:c.19097G>T
NM_001271208.1:c.19097G>T
NM_004543.4:c.13994G>T
NM_001271208.2:c.19097G>T
NM_004543.5:c.13994G>T
NM_001164507.2:c.19097G>T
More

Pathogenic

Met criteria codes 4
PS3 PP4 PP3 PM3_Very Strong
Not Met criteria codes 4
PM2 BA1 BS1 BP4

Evidence Links 0

Expert Panel

Criteria Specification Information

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Congenital Myopathies VCEP
The c.19097G>T (p.Ser6366Ile) variant in NEB is a missense variant predicted to cause substitution of serine by isoleucine at amino acid 6366. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0004723 (30/63518 alleles) in the European (Finnish) population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (MAF≥0.000237) for BS1. However, this variant is excluded from the application of BA1/BS1 by the ClinGen Congenital Myopathies VCEP as it is a well established pathogenic variant. The computational predictor REVEL gives a score of 0.829, which is above the threshold of 0.7, evidence that correlates with impact to NEB function (PP3). This variant has been detected in 10 individuals with nemaline myopathy. Eight of those individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 2 of those were confirmed in trans by family testing. Two individuals were homozygous for the variant (PMIDs: 25205138, 15336686, 17525139) (PM3_VeryStrong). At least one patient with this variant displayed nemaline rods, which is highly specific for nemaline myopathy (PP4, PMID: 17525139). A typical NM mouse model with compound heterozygous variants (p.Ser6366Ile and NebΔExon55) mimics features found in NM patients such as growth-retardation, muscle weakness, and atrophic muscles that contain nemaline rods and structural features consistent with NM. The S6366I-Homozygous model has a phenotype that develops with age and appears to share similarities with Finnish distal myopathy patients (PMID: 32483185)(PS3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM3_VeryStrong, PS3, PP3, PP4. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024)
Met criteria codes
PS3
A typical NM mouse model with compound heterozygous variants (p.Ser6366Ile and NebΔExon55) mimics features found in NM patients such as growth-retardation, muscle weakness, and atrophic muscles that contain nemaline rods and structural features consistent with NM. The S6366I-Homozygous model has a phenotype that develops with age and appears to share similarities with Finnish distal myopathy patients (PMID: 32483185)
PP4
At least one patient with this variant displayed nemaline rods, which is highly specific for nemaline myopathy (PMID: 17525139)
PP3
REVEL gives a score of 0.829, which is above the threshold of 0.7, evidence that correlates with impact to NEB function
PM3_Very Strong
detected in 10 individuals with nemaline myopathy. Eight of those individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 2 of those were confirmed in trans by family testing. Two individuals were homozygous for the variant (PMIDs: 25205138, 15336686, 17525139)
Not Met criteria codes
PM2
The gnomAD v4.1.0 highest population MAF is 0.0004723 (30/63518 alleles) in Finnish European which does not meet the threshold for PM2_P application
BA1
The gnomAD v4.1.0 highest population MAF is 0.0004723 (30/63518 alleles) in Finnish European but is excluded from the BA1/BS1 as it is a well-established pathogenic variant
BS1
The gnomAD v4.1.0 highest population MAF is 0.0004723 (30/63518 alleles) in Finnish European but is excluded from the BA1/BS1 as it is a well-established pathogenic variant
BP4
REVEL gives a score of 0.829, which is above the threshold of 0.7, evidence that correlates with impact to NEB function
Curation History
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