Evidence Repository - GenboreeKB

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_000256.3(MYBPC3):c.1484G>A (p.Arg495Gln)

CA010464

164113 (ClinVar)

Gene: MYBPC3 (HGNC:4607)

Condition: hypertrophic cardiomyopathy (MONDO:0005045)

Inheritance Mode: Autosomal dominant inheritance

UUID: 632dba69-eba4-43bd-aeb8-8e6a23dab49b

Approved on: 2025-11-14

Published on: 2025-11-14

HGVS expressions

NM_000256.3:c.1484G>A

NM_000256.3(MYBPC3):c.1484G>A (p.Arg495Gln)

NC_000011.10:g.47342718C>T

CM000673.2:g.47342718C>T

NC_000011.9:g.47364269C>T

CM000673.1:g.47364269C>T

NC_000011.8:g.47320845C>T

NG_007667.1:g.14985G>A

ENST00000545968.6:c.1484G>A

ENST00000256993.8:c.1484G>A

ENST00000399249.6:c.1484G>A

ENST00000544791.1:c.1484G>A

ENST00000545968.5:c.1484G>A

Likely Pathogenic

PS4_Moderate PM1 PP1_Strong

BA1 BS1 BS3 BP4 PS1 PS3 PP2 PP3 PM2

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYBPC3 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The NM_000256.3(MYBPC3):c.1484G>A (p.Arg495Gln). This variant has been reported in individuals with HCM and other cardiomyopathies (ClinVar Variation ID: 164113) and has also been identified in 5 out of 112974 (0.009% FAF 95% CI) of European chromosomes in gnomAD (https://gnomad.broadinstitute.org/; v.2.1). The variant is statistically increased in individuals with HCM compared to controls (OR lower 95% CI>10), therefore, the PS4 criterion has been applied at moderate strength (PS4_Moderate) and the PM2_Supporting criterion has not been applied. This variant segregated with disease in >7 affected individuals with HCM from at least 4 families (PP1_Strong; Maron 2011 PMID: 21185001, Agarwal 2015 PMID: 26271555, Mattos 2016 Year PMID: 27737317, Ross 2017 PMID: 28615295). This variant lies in a region of the protein where variants are statistically more likely to be disease-associated (PM1_Strength; Walsh 2019 PMID: 30696458). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein (REVEL score <0.7). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner based on PS4_Moderate, PP1_Strong and PM1.

PS4_Moderate

Walsh (OGML+ LMM) : 14/6179 cases, gnomad 2.1 (NFE) : 5/112974 alleles OR calculations: 14 in 6179 case genotypes vs 5 in 56487 control genotypes gives an odds ratio of 25.65 (95%CI=9.24-71.24) Lower bound CI: Strong 95%CI=9.24 (threshold for strong ≥20) Moderate 95%CI=9.24 (threshold for moderate ≥10) Supporting 95%CI=9.24 (threshold for supporting ≥5) The lower bound 95%CI is greater than 5 (95%CI=9.24). Therefore PS4 is set to PS4_Supporting. Given that this is just shy of 10, and gnomad 4.1.0 will get this to Moderate, will upgrade to PS4_moderate (this was what was denoted in the pilot variant excel sheet summary as well)

PM1

This variant lies in a region of the protein where variants are statistically more likely to be disease-associated (PM1_Strength; Walsh 2019 PMID: 30696458).

PP1_Strong

see below

BA1

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

BS1

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

BS3

no functional studies

BP4

Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein.

PS1

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

PS3

no functional studies

PP2

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

PP3

Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein.

PM2

Variant is present in gnomAD v2.1.1 but does not meet threshold for PM2_Supporting.

Curation History

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