Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001164508.2(NEB):c.22144A>C (p.Thr7382Pro)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA1906766

506284 (ClinVar)

Gene: NEB

Condition: nemaline myopathy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: fdc5cc5f-5822-45d1-a94c-b5e124392663

Approved on: 2024-08-07

Published on: 2024-10-01

HGVS expressions

NM_001164508.2:c.22144A>C

NM_001164508.2(NEB):c.22144A>C (p.Thr7382Pro)

NC_000002.12:g.151525975T>G

CM000664.2:g.151525975T>G

NC_000002.11:g.152382489T>G

CM000664.1:g.152382489T>G

NC_000002.10:g.152090735T>G

NG_009382.2:g.213513A>C

ENST00000434685.6:c.1605-702A>C

ENST00000690043.1:c.4995A>C

ENST00000693000.1:n.1169A>C

ENST00000693286.1:c.843A>C

ENST00000397345.8:c.22144A>C

ENST00000427231.7:c.22144A>C

ENST00000172853.14:c.17041A>C

ENST00000397345.7:c.22144A>C

ENST00000409198.5:c.17041A>C

ENST00000413693.5:c.6334A>C

ENST00000427231.6:c.22144A>C

ENST00000434685.5:c.12A>C

ENST00000603639.5:c.22144A>C

ENST00000604864.5:c.22144A>C

ENST00000618972.4:c.22249A>C

NM_001164507.1:c.22144A>C

NM_001164508.1:c.22144A>C

NM_001271208.1:c.22249A>C

NM_004543.4:c.17041A>C

NM_001271208.2:c.22249A>C

NM_004543.5:c.17041A>C

NM_001164507.2:c.22144A>C

Pathogenic

PP4 PP1_Strong PM3_Strong

PS3 PP3 PM2 BA1 BS1 BP4

Evidence Links 1

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Congenital Myopathies VCEP

The c.22144A>C p.(Thr7382Pro) variant in NEB is a missense variant predicted to cause substitution of Threonine by Proline at amino acid 7382. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001406 (9/64028 alleles) in the Finnish population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a SCORE of 0.286 which is neither above nor below the thresholds predicting a damaging or benign impact on NEB function. This variant has been detected in 4 individuals with typical nemaline myopathy. Two of those individuals were compound heterozygous with an LP/P variant, phase confirmed and two were homozygous (PMID:16917880, 17525139) (PM3_Strong). At least two individuals with this variant displayed nemaline bodies (confirmed by electron microscopy), which is highly specific for nemaline myopathy (PP4, PMID:17525139). The variant has been reported to segregate with nemaline myopathy in 3 individuals with biallelic occurrence and 5 unaffected family members did not have biallelic occurrence in 2 families (PP1_Strong; PMID:17525139). Binding experiments for the nebulin super repeats, using co-sedimentation and GST (glutathione-S-transferase) pull-down assays (PMID: 25110572) showed weaker binding than WT proteins to tropomyosin. However, this assay does not meet the requirements for use by the ClinGen Congenital Myopathies VCEP. 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_Strong, PP1_Strong, PP4. (Congenital Myopathies VCEP specifications version 1; 8/7/2024)

PP4

At least two individuals with this variant displayed nemaline bodies (confirmed by electron microscopy), which is highly specific for nemaline myopathy (PMID:17525139)

PP1_Strong

The variant has been reported to segregate with nemaline myopathy in 3 individuals with biallelic occurrence and 5 unaffected family members did not have biallelic occurrence in 2 families.

PM3_Strong

This variant has been detected in 4 individuals with typical nemaline myopathy. Two of those individuals were compound heterozygous with an LP/P variant, phase confirmed and two were homozygous (PMID: 16917880, 17525139)

PS3

Binding experiments for the nebulin super repeats, using co-sedimentation and GST (glutathione-S-transferase) pull-down assays (PMID: 25110572 ) showed weaker binding than WT proteins to tropomyosin. However, this assay does not meet the requirements for use by the ClinGen Congenital Myopathies VCEP.

PP3

The computational predictor REVEL gives a SCORE of 0.286 which is neither above nor below the thresholds predicting a damaging or benign impact on NEB function).

PM2

The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001406 (9/64028 alleles) in the Finnish population. PM2_Supporting, BS1, and BA1 are not met.

BA1

The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001406 (9/64028 alleles) in the Finnish population. PM2_Supporting, BS1, and BA1 are not met.

BS1

The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001406 (9/64028 alleles) in the Finnish population. PM2_Supporting, BS1, and BA1 are not met.

BP4

The computational predictor REVEL gives a SCORE of 0.286 which is neither above nor below the thresholds predicting a damaging or benign impact on NEB function).

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.