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.4729G>A (p.Ala1577Thr)

Curation Version - 1.0
Curation History
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CA024459

65923 (ClinVar)

Gene: RYR1

Condition: RYR1-related myopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: dfed8be2-fb3d-47be-ad3d-f6822f70faec

Approved on: 2024-08-27

Published on: 2025-01-03

HGVS expressions

NM_000540.3:c.4729G>A

NM_000540.3(RYR1):c.4729G>A (p.Ala1577Thr)

NC_000019.10:g.38483311G>A

CM000681.2:g.38483311G>A

NC_000019.9:g.38973951G>A

CM000681.1:g.38973951G>A

NC_000019.8:g.43665791G>A

NG_008866.1:g.54612G>A

ENST00000599547.6:c.4729G>A

ENST00000359596.8:c.4729G>A

ENST00000355481.8:c.4729G>A

ENST00000359596.7:c.4729G>A

ENST00000360985.7:c.4726G>A

NM_000540.2:c.4729G>A

NM_001042723.1:c.4729G>A

NM_001042723.2:c.4729G>A

Uncertain Significance

PP3

PS4 BA1 PM2 PM3 BS1 BP4

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 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Congenital Myopathies VCEP

The c.4729G>A variant in RYR1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 1577. The filtering allele frequency (the lower threshold of the 95% CI of 8/73780) of the c.4729G>A variant in RYR1 is 0.00006033 for African/African American chromosomes by gnomAD v4.1 (BA1, BS1, PM2 not met). The computational predictor REVEL gives a score of 0.908, which is above the threshold of 0.7, evidence that correlates with impact to RYR1 function (PP3). This variant has been reported in 2 probands with RYR1-related myopathy and has been detected in 1 individual with RYR1-related myopathy, compound heterozygous for the variant and a rare VUS, confirmed in trans by family testing (c.14818G>A (p.A4940T), SCV000852639.1). In summary, this variant meets the criteria to be classified as uncertain significance for RYR1-related myopathy with multiple patterns of inheritance reported, based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PP3. (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024)

PP3

The computational predictor REVEL gives a score of 0.908, which is above the threshold of 0.7, evidence that correlates with impact to RYR1 function (PP3).

PS4

This variant has been reported in 2 probands with RYR1-related myopathy (PMID: 16940308, 17365175).

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM2

The filtering allele frequency (the lower threshold of the 95% CI of 8/73780) of the c.4729G>A variant in RYR1 is 0.00006033 for African/African American chromosomes by gnomAD v4.1 (as inheritance is unclear, using BA1/BS1 AR cutoffs and no population codes met).

PM3

This variant has been detected in 1 individual with RYR1-related myopathy, compound heterozygous for the variant and a rare VUS, confirmed in trans by family testing (c.14818G>A (p.A4940T), SCV000852639.1).

BS1

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

Curation History

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