Variant: NM_000540.3(RYR1):c.8888T>C (p.Leu2963Pro)

CA072871

642707 (ClinVar)

Gene: RYR1

Condition: RYR1-related myopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: fc796c12-2590-4d0b-8706-9d9687475c7d

Approved on: 2024-08-07

Published on: 2024-10-01

HGVS expressions

NM_000540.3:c.8888T>C
NM_000540.3(RYR1):c.8888T>C (p.Leu2963Pro)
NC_000019.10:g.38507783T>C
CM000681.2:g.38507783T>C
NC_000019.9:g.38998423T>C
CM000681.1:g.38998423T>C
NC_000019.8:g.43690263T>C
NG_008866.1:g.79084T>C
ENST00000599547.6:c.8888T>C
ENST00000359596.8:c.8888T>C
ENST00000355481.8:c.8888T>C
ENST00000359596.7:c.8888T>C
ENST00000360985.7:c.8885T>C
ENST00000594335.5:c.2340T>C
NM_000540.2:c.8888T>C
NM_001042723.1:c.8888T>C
NM_001042723.2:c.8888T>C

Pathogenic

• Met criteria codes: PM3_Very Strong PP1 PP3 PM2_Supporting PS3_Supporting

• Not Met criteria codes: BP5 BP7 BP3 BP2 BP4 BP1 PS4 PS2 PS1 PP4 PP2 PM1 PM4 PM5 PM6 BS2 BS4 BS3 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 RYR1 Version 1.0.0

Evidence submitted by expert panel

Congenital Myopathies VCEP

The NM_000540.3:c.8888T>C variant in RYR1 is a missense variant predicted to cause substitution of leucine by proline at amino acid 2963 (p.Leu2963Pro). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000002478 (4/1179858 alleles) in the European (non-Finnish) population (PM2_Supporting). The REVEL computational prediction analysis tool gives a score of 0.841, which is above the threshold necessary to apply PP3. This variant has been reported in five probands with RYR1-related myopathy (PM3_VeryStrong). Of those individuals, four were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (c.6721C>T(p.Arg2241Ter), c.14416A>G(p.Asn4806Asp), c.46-1G>A, ) and three of those were confirmed in trans (PMIDs:24951453, 27234031; SCV003761249.1; VCEP internal data). One individual was homozygous for the variant (PMIDs:23826317). The variant has been reported to segregate in one affected sibling from a family (PP1, PMID: 24951453). Western blot analysis of a deltoid muscle extract revealed a strong reduction of the RYR1 protein level by 37% in patient cells compared to a healthy age-matched control, supporting that the variant reduced protein expression (PS3_Supporting, PMID:23826317). In summary, the variant meets the 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, PS3_Supporting, PM2_Supporting, PP1, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024).

Met criteria codes

• PM3_Very Strong: The variant was reported in 3 probands from 3 publications (PMIDs: 23826317, 24951453, 27234031). 2 more probands were reported through internal data (Rare Disease Group Internal Data (SCV003761249.1), VCEP internal data)
• PP1: The variant segregated in an affected sibling in one family (PMID:24951453)
• PP3: The REVEL score is 0.841, which is above the threshold of 0.7 to apply PP3
• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1.0 is 0.000002478 (4/1179858 alleles) in the European (non-Finnish) population.
• PS3_Supporting: In vitro functional studies provide some evidence that the Leu2963Pro variant may slightly impact protein function

Not Met criteria codes

• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline