Evidence Repository
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_000540.3(RYR1):c.14173G>C (p.Val4725Leu)

CA308120058

571399 (ClinVar)

Gene: RYR1
Condition: RYR1-related myopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 026d53a8-c475-4a8b-92ee-42e7539524ae
Approved on: 2024-08-27
Published on: 2025-01-03

HGVS expressions

NM_000540.3:c.14173G>C
NM_000540.3(RYR1):c.14173G>C (p.Val4725Leu)
NC_000019.10:g.38577918G>C
CM000681.2:g.38577918G>C
NC_000019.9:g.39068558G>C
CM000681.1:g.39068558G>C
NC_000019.8:g.43760398G>C
NG_008866.1:g.149219G>C
ENST00000593677.2:c.1109G>C
ENST00000688602.1:c.2506G>C
ENST00000689936.1:c.2478G>C
ENST00000359596.8:c.14173G>C
ENST00000355481.8:c.14158G>C
ENST00000359596.7:c.14173G>C
ENST00000360985.7:c.14155G>C
NM_000540.2:c.14173G>C
NM_001042723.1:c.14158G>C
NM_001042723.2:c.14158G>C
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Uncertain Significance

Met criteria codes 1
PM2_Supporting
Not Met criteria codes 4
BA1 PP3 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 RYR1 Version 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Congenital Myopathies VCEP
The c.14173G>C variant in RYR1 is a missense variant predicted to cause substitution of valine by leucine at amino acid 4725. The highest population minor allele frequency in gnomAD v4.1 is 0.00001667 (1/59980 alleles) in the Admixed American population, which is lower than the ClinGen Congenital Myopathies VCEP threshold (absent, 1 allele allowed) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.661, which is neither above nor below the thresholds predicting a damaging or benign impact on RYR1 function. In summary, the variant meets the criteria to be classified as uncertain significance for RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_Supporting (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024).
Met criteria codes
PM2_Supporting
The highest population minor allele frequency in gnomAD v4.1 is 0.00001667 (1/59980 alleles) in the Admixed American population, which is lower than the ClinGen Congenital Myopathies VCEP threshold (absent, 1 allele allowed) for PM2_Supporting, meeting this criterion (PM2_Supporting).
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
The computational predictor REVEL gives a score of 0.661, which is neither above nor below the thresholds predicting a damaging or benign impact on RYR1 function.
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
The computational predictor REVEL gives a score of 0.661, which is neither above nor below the thresholds predicting a damaging or benign impact on RYR1 function.
Curation History
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