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_000540.3(RYR1):c.14928C>G (p.Phe4976Leu)

CA024278

201154 (ClinVar)

Gene: RYR1 (HGNC:6261)

Condition: RYR1-related myopathy (MONDO:0100150)

Inheritance Mode: Autosomal recessive inheritance

UUID: f5a7c288-042b-4beb-800e-ac3fce420d14

Approved on: 2026-01-12

Published on: 2026-07-20

HGVS expressions

NM_000540.3:c.14928C>G

NM_000540.3(RYR1):c.14928C>G (p.Phe4976Leu)

NC_000019.10:g.38586150C>G

CM000681.2:g.38586150C>G

NC_000019.9:g.39076790C>G

CM000681.1:g.39076790C>G

NC_000019.8:g.43768630C>G

NG_008866.1:g.157451C>G

ENST00000593677.2:c.1864C>G

ENST00000688602.1:c.3261C>G

ENST00000689936.1:c.3233C>G

ENST00000692547.1:n.321C>G

ENST00000359596.8:c.14928C>G

ENST00000355481.8:c.14913C>G

ENST00000359596.7:c.14928C>G

ENST00000360985.7:c.14910C>G

NM_000540.2:c.14928C>G

NM_001042723.1:c.14913C>G

NM_001042723.2:c.14913C>G

Pathogenic

PP1_Moderate PM3_Very Strong PP3

PM2 BA1 BS1 BP4 BP1 PP2

Evidence Links 0

Expert Panel

Congenital Myopathies VCEP

Criteria Specification Information

Criteria Specification: ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RYR1 Version 2.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Congenital Myopathies VCEP

The variant NM_000540.3:c.14928C>G in RYR1 is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 4976 (p.Phe4976Leu). The highest minor allele frequency in gnomAD v4.1.0 is 0.00001102 (13/1180036 alleles) in non-Finnish European (PM2_Supporting, BS1, and BA1 are not met). The REVEL computational prediction analysis tool produced a score of 0.897, which is above the threshold of 0.7, evidence that correlates with impact to RYR1 function (PP3). This variant has been reported in homozygosity in two probands and in compound heterozygosity in six probands with clinical features compatible with RYR1-related myopathy (PM3_VeryStrong; PMIDs: 24706162, 25882082, 30155320, 31134282; Ambry Genetics, SCV000262905.5; Labcorp Genetics, SCV000932617.6; VCEP internal contributors). The variant segregated with disease in two additional family members (PP1_Moderate; PMIDs: 25882082, 30155320). In summary, the variant meets criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PM3_VeryStrong, PP1_Moderate, PP3 (ClinGen Congenital Myopathies VCEP specifications version 2.0.0).

PP1_Moderate

The variant segregated with disease in two additional family members (PP1_Moderate; PMIDs: 25882082, 30155320).

PM3_Very Strong

This variant has been reported in eight probands of which it was homozygous in two probands and compound heterozygous in six probands with clinical features compatible with RYR1-related myopathy (PM3_VeryStrong; PMIDs: 24706162, 25882082, 30155320, 31134282; Ambry Genetics, SCV000262905.5; Labcorp Genetics, SCV000932617.6; VCEP internal contributors).

PP3

The REVEL score is 0.897, which is above the threshold of 0.7 to apply PP3.

PM2

The highest minor allele frequency in gnomAD v4.1.0 is 0.00001102 (13/1180036 alleles) in non-Finnish European which meets no population codes.

BA1

The highest minor allele frequency in gnomAD v4.1.0 is 0.00001102 (13/1180036 alleles) in non-Finnish European which meets no population codes.

BS1

The highest minor allele frequency in gnomAD v4.1.0 is 0.00001102 (13/1180036 alleles) in non-Finnish European which meets no population codes.

BP4

The REVEL score is 0.897, which is above the threshold of 0.7 to apply PP3.

BP1

Both missense and truncating variants in RYR1 are disease-causing.

PP2

RYR1 is not a gene that is constrained for missense variation. Hence PP2 is not applicable.

Curation History

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