Variant: NM_000258.3(MYL3):c.460C>T (p.Arg154Cys)

Version: 1.0
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CA013849

43124 (ClinVar)

Gene: MYL3 (HGNC:4634)

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 4ca2eb66-cce1-41af-ad2e-46d4ffe0abfe

Approved on: 2025-11-14

Published on: 2025-11-14

HGVS expressions

NM_000258.3:c.460C>T
NM_000258.3(MYL3):c.460C>T (p.Arg154Cys)
NC_000003.12:g.46859496G>A
CM000665.2:g.46859496G>A
NC_000003.11:g.46900986G>A
CM000665.1:g.46900986G>A
NC_000003.10:g.46875990G>A
NG_007555.2:g.27674C>T
ENST00000431168.2:c.460C>T
ENST00000292327.6:c.460C>T
ENST00000653454.1:c.460C>T
ENST00000654597.1:c.460C>T
ENST00000655244.1:n.682C>T
ENST00000662933.1:c.460C>T
ENST00000664891.1:n.418C>T
ENST00000292327.4:c.460C>T
ENST00000395869.5:c.460C>T
NM_000258.2:c.460C>T

Uncertain Significance

• Met criteria codes: PS4_Supporting PP3

• Not Met criteria codes: PS2 PS3 PS1 PP1 PP2 PM6 PM2 PM1 PM5 BA1 BS4 BS3 BS1 BP5 BP2 BP4

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYL3 Version 1.0.0

Evidence submitted by expert panel

Cardiomyopathy VCEP

NM_000258.3(MYL3):c.460C>T (p.Arg154Cys). This variant has been reported in individuals with HCM and other cardiomyopathies (ClinVar Variation ID 43124) and has also been identified in 4 out of 282804 (0.025% FAF 95% CI) of pan-ethnic chromosomes in gnomAD (https://gnomad.broadinstitute.org/; v2.1). The 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. MYL2-specific ACMG/AMP criteria applied: PS4_Supporting, PP3.

Met criteria codes

• PS4_Supporting: Walsh 2017: 1/1535 Oxford, 2/2650 LMM (african american, asian, unspecified, decided to use global gnomad) gnoMAD: 2/129136 NFE 4/282804 global 3 in 4185 case genotypes vs 4 in 141402 control genotypes gives an odds ratio of 25.36 (95%CI=5.67-113.34) Lower bound CI: Strong 95%CI=5.67 (threshold for strong ≥20) Moderate 95%CI=5.67 (threshold for moderate ≥10) Supporting 95%CI=5.67 (threshold for supporting ≥5) The lower bound 95%CI is greater than 5 (95%CI=5.67). Therefore PS4 is set to PS4_Supporting
• PP3: Computational prediction tools and conservation analyses suggest that this variant may impact the protein (PP3; REVEL score ≥0.70)

Not Met criteria codes

• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: 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
• PP1: 1 seg LMM , not counting code
• PP2: n/a for MYL3
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: AF = 0.008%, 95% CI =0.02% (gnomad 4 not met, just above 0.004%)
• PM1: n/a for MYL3
• PM5: 2 other variants in this codon are VUS
• BA1: 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 studies
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: 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