Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000257.4(MYH7):c.427C>T (p.Arg143Trp)

CA014751

164401 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: a5d5ca4d-e48c-4e60-8ec0-83141a9d091a
Approved on: 2025-11-13
Published on: 2025-11-13

HGVS expressions

NM_000257.4:c.427C>T
NM_000257.4(MYH7):c.427C>T (p.Arg143Trp)
NC_000014.9:g.23432714G>A
CM000676.2:g.23432714G>A
NC_000014.8:g.23901923G>A
CM000676.1:g.23901923G>A
NC_000014.7:g.22971763G>A
NG_007884.1:g.7948C>T
ENST00000355349.4:c.427C>T
ENST00000355349.3:c.427C>T
NM_000257.3:c.427C>T
More

Pathogenic

Met criteria codes 5
PS4 PM2_Supporting PP3 PP1_Strong PM5_Supporting
Not Met criteria codes 15
BS4 BS3 BS1 PVS1 BP5 BP7 BP4 BP3 PS3 PS2 PS1 BA1 PM6 PM1 PM4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYH7 Version 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
NM_000257.4(MYH7):c.427C>T (p.Arg143Trp) - This variant has been reported in numerous individuals with HCM, including 1 individual in which it was observed in the homozygous state (LMM data, OMGL data, PMIDs: 12820698, 12974739, 21839045, 22455086, 23711808, 24510615, 25086479, 28193612, 28771489, 30588760, 32344918) and is statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI >20]. This variant segregated with disease in >9 affected relatives from three families (PMID: 28771489, GeneDx pers. comm., OMGL pers. comm.). Therefore, the PS4_Strong and PP1_Strong criteria have been applied. It was also identified in 2 infants with DCM that had loss of function variants in MYH7 and both variants segregated with DCM in one affected infant sibling (Ambry pers. comm; LMM pers. comm.). This variant is present in gnomAD (v4.1.0), but did meet the threshold for PM2_Supporting. Another variant at this codon (p.Arg143Gln) has been identified in individuals with HCM and is classified as likely pathogenic by this VCEP (PM5_Supporting). Computational prediction tools suggest that this variant may impact the protein (REVEL score >0.7; PP3). In summary, this variant is classified as Pathogenic for HCM in an autosomal dominant manner based on PS4, PP1_Strong, PM2_Supporting, PM5_Supporting, and PP3.
Met criteria codes
PS4
Kapplinger 6 in 2178 case genotypes vs 20 in 807018 control genotypes gives an odds ratio of 111.46 (95%CI=44.72-277.82). gnomAD v4 global since observed in multiple ancestries. The lower bound 95%CI is greater than 20 (95%CI=44.72). Therefore PS4 is set to PS4_Strong. OMGL + HCMR 8 in 5281 case genotypes vs 20 in 807018 control genotypes gives an odds ratio of 61.22 (95%CI=26.95-139.04). gnomAD v4 global since observed in multiple ancestries. The lower bound 95%CI is greater than 20 (95%CI=26.95). Therefore PS4 is set to PS4_Strong Multiple other case reports that are not accounted for within OR. This variant has been reported in numerous individuals with HCM, including 1 individual in which it was observed in the homozygous state (LMM data, OMGL data, PMIDs: 12820698, 12974739, 21839045, 22455086, 23711808, 24510615, 25086479, 28193612, 28771489, 30588760, 32344918) and is statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI >20]. This variant segregated with disease in >9 affected relatives from three families (PMID: 28771489, GeneDx pers. comm., OMGL pers. comm.). Therefore, PS4_Strong and PP1_Strong criteria have been applied.
PM2_Supporting
This variant is present in gnomAD (both v2.1.1 and v4.1.0), but did meet the threshold for PM2_Supporting.
PP3
Computational prediction tools suggest that this variant may impact the protein (REVEL score >0.7; PP3).
PP1_Strong
7 meioses from clinical lab data (5 OMGL and 2 GeneDx), plus 3 additional reported seg in lit but without family structure. This variant segregated with disease in >9 affected relatives from three families (PMID: 28771489, GeneDx pers. comm., OMGL pers. comm.).
PM5_Supporting
p.R143Q does not meet pathogenic criteria by MYH7 EP rules.[PM2, PS4 (>15 HCM probands in lit)]. Note I do not have shared clinical data for this alteration, if strong segregation data, could get to pathogenic, but that seems unlikely. NM_000257.4(MYH7):c.428G>A (p.Arg143Gln) - 3* LP NM_000257.4(MYH7):c.427C>G (p.Arg143Gly) - 2* LP
Not Met criteria codes
BS4
Seen in unaffected relatives in 30588760 (a in pedigree 1, 4 in pedigree 2), but ages unknown.
BS3
No such studies.
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
Missense change
BP5
Cases with alternate molecular basis for disease are either very severe (2 infant onset compound hets with DCM) or we have no details on severity. No real concern given the data we have.
BP7
missense change
BP4
see above
BP3
Missense change
PS3
No such studies
PS2
n/a
PS1
No such alteration reported
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
n/a
PM1
5' of head domain
PM4
Missense change
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.