Variant: NM_000256.3(MYBPC3):c.2573G>A (p.Ser858Asn)

Version: 1.0
JSON-LD PDF

CA012667

164070 (ClinVar)

Gene: MYBPC3 (HGNC:4607)

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 3a6aea26-e296-4bd1-8eb3-ea6bf17777ab

Approved on: 2025-11-14

Published on: 2025-11-14

HGVS expressions

NM_000256.3:c.2573G>A
NM_000256.3(MYBPC3):c.2573G>A (p.Ser858Asn)
NC_000011.10:g.47337420C>T
CM000673.2:g.47337420C>T
NC_000011.9:g.47358971C>T
CM000673.1:g.47358971C>T
NC_000011.8:g.47315547C>T
NG_007667.1:g.20283G>A
ENST00000545968.6:c.2573G>A
ENST00000256993.8:c.2573G>A
ENST00000399249.6:c.2573G>A
ENST00000544791.1:c.*78G>A
ENST00000545968.5:c.2573G>A

Uncertain Significance

• Met criteria codes: PP3 PS4_Supporting

• Not Met criteria codes: PS2 PS3 PS1 BA1 PP2 PM6 PM2 PM1 PM5 BS3 BS1 BP2 BP4

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

Evidence submitted by expert panel

Cardiomyopathy VCEP

NM_000256.3(MYBPC3):c.2573G>A (p.Ser858Asn). This variant has been in individuals with HCM (ClinVar Variation ID: 164070) and has also been identified in 2 out of 124800 (0.005% FAF 95% CI) of European chromosomes in gnomAD (https://gnomad.broadinstitute.org/; v.2.1). This variant is statistically increased in individuals with HCM compared to controls (OR lower 95% CI>5), therefore, the PS4 criterion has been applied at supporting strength (PS4_Supporting) and the PM2_Supporting criterion has not been applied. Computational prediction tools and conservation analyses suggest that this variant may impact the protein (PP3; REVEL score ≥0.70). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner based on PS4_Supporting, and PP3.

Met criteria codes

• PP3: Computational prediction tools and conservation analyses suggest that this variant may impact the protein (PP3; REVEL score ≥0.70)
• PS4_Supporting: Walsh 2017 : 4 LMM 2 OMGL 6/6179 cases vs 2/124800 NFE gnomad 2.1 6 in 6179 case genotypes vs 2 in 62400 control genotypes gives an odds ratio of 30.32 (95%CI=6.12-150.28) Lower bound CI: Strong 95%CI=6.12 (threshold for strong ≥20) Moderate 95%CI=6.12 (threshold for moderate ≥10) Supporting 95%CI=6.12 (threshold for supporting ≥5) The lower bound 95%CI is greater than 5 (95%CI=6.12). Therefore PS4 is set to PS4_Supporting. Decipher 3/14976 alleles, similar OR Note that in gnomad 4.1 18/1174272 NFE PS4_moderate

Not Met criteria codes

• PS2: no denovo
• PS3: no studies
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: n/a for MYBPC3
• PM6: no de novo
• PM2: This variant has been identified in been identified in 2 out of 124800 (0.005% FAF 95% CI) of European chromosomes (> 0.004%)
• PM1: not in codons 485-502 & 1248- 1266
• PM5: variants at same codon do not meet criteria for LP/P
• BS3: no studies
• BS1: 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: Computational prediction tools and conservation analyses suggest that this variant may impact the protein (PP3; REVEL score ≥0.70)