Variant: NM_000257.4(MYH7):c.2785_2787GAG[2] (p.Glu931del)

42934 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 5fe5fef0-e52a-4616-8e14-0b7ae7e8da51

HGVS expressions

NM_000257.4:c.2785_2787GAG[2]
NM_000257.4(MYH7):c.2785_2787GAG[2] (p.Glu931del)
NM_000257.4(MYH7):c.2785GAG[2] (p.Glu931del)

Likely Pathogenic

• Met criteria codes: PM2 PP1_Moderate PS4_Moderate PM4_Supporting

• Not Met criteria codes: PS2 PS1 PS3 BA1 PP3 PVS1 PM6 PM1 PM5 BS3 BS4 BS1 BP5 BP2 BP7 BP4

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cardiomyopathy VCEP

The NM_000257.3(MYH7):c.2791_2793delGAG (p.Glu931del) variant has been reported in at least 8 individuals with HCM (PS4_Moderate; Tesson 1998 PMID:9829907; Richard 2013 PMID:12707239; Walsh 2017 PMID:27532257; Norrish 2019 PMID:31006259; GeneDx pers. comm., Invitae pers. comm., LMM pers. comm., OMGL pers.comm.) and segregated with disease in 5 affected individuals with HCM in 1 family (PP1_Moderate; Tesson 1998 PMID:9829907). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant is a deletion of 1 amino acid at position 931 and is not predicted to alter the protein reading-frame. Given that only 1 amino acid has been deleted, the expert panel felt that adjusting to supporting evidence would be more appropriate in this case (PM4_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_ Moderate; PP1_Moderate; PM2; PM4_Supporting.

Met criteria codes

• PM2: Absent from gnomAD with good coverage
• PP1_Moderate: 5 segregations
• PS4_Moderate: At least 7 probands with HCM. Did not count probands that are likely duplicates.
• PM4_Supporting: Inframe indel, in a non-repeat region

Not Met criteria codes

• PS2: No reports of de novo inheritance
• PS1: N/A for in-frame deletion
• PS3: no functional studies reported
• BA1: Absent from gnomAD
• PP3: N/A for in-frame deletion
• PVS1: N/A for in-frame deletion
• PM6: No reports of de novo inheritance
• PM1: does not apply to in-frame deletion (is this true?)
• PM5: N/A for in-frame deletion
• BS3: no functional studies reported
• BS4: No non-segregations reported
• BS1: Absent from gnomAD
• BP5: Not found with another pathogenic variant
• BP2: Not observed with another pathogenic variant
• BP7: N/A for in-frame deletion
• BP4: N/A for in-frame deletion

Approved on: 2021-11-23

Published on: 2021-12-09