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]
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  • See Evidence submitted by expert panel for details.

Variant: NM_000257.4(MYH7):c.550A>C (p.Lys184Gln)

CA016180

181312 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 4d11a87c-255f-4e05-b684-ea8f22214ca3
Approved on: 2021-12-01
Published on: 2021-12-09

HGVS expressions

NM_000257.4:c.550A>C
NM_000257.4(MYH7):c.550A>C (p.Lys184Gln)
NC_000014.9:g.23431850T>G
CM000676.2:g.23431850T>G
NC_000014.8:g.23901059T>G
CM000676.1:g.23901059T>G
NC_000014.7:g.22970899T>G
NG_007884.1:g.8812A>C
ENST00000355349.4:c.550A>C
ENST00000355349.3:c.550A>C
NM_000257.3:c.550A>C

Uncertain Significance

Met criteria codes 2
PP3 PM2
Not Met criteria codes 24
PVS1 BA1 BP1 BP3 BP7 BP4 BP5 BP2 BS2 BS3 BS4 BS1 PP1 PP2 PP4 PM5 PM4 PM1 PM6 PS3 PM3 PS1 PS2 PS4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The NM_000257.4(MYH7):c.550A>C (p.Lys184Gln) variant has been identified in at least 4 individuals with LVNC (Miller 2017 PMID:29212898; GeneDx pers. comm.; Invitae pers. comm.), 1 individual with HCM and LVNC (Ambry pers. comm.), 1 individual with HCM who carried another pathogenic variant in MYH7 (GeneDx pers. comm.) and 1 individual with sudden cardiac death. Additionally, this variant has segregated with LVNC in 6 affected relatives from 2 families (GeneDx pers. comm.). While this variant has been reported in multiple phenotypes, there is conflicting evidence on whether isolated LVNC is a Mendelian disease and therefore those cases without additional cardiomyopathy features are not currently being counted. Therefore, the current evidence is currently insufficient to apply the PS4 or the PP1 criteria for the HCM phenotypes. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM, but location in this region cannot be used to support pathogenicity for other phenotypes ( Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PP3.
Met criteria codes
PP3
REVEL score 0.92
PM2
Variant is absent from gnomAD with good coverage.
Not Met criteria codes
PVS1
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
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
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
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
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
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
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
Per GeneDx ClinVar entry "shown to segregate with left ventricular non-compaction (LVNC) in several affected relatives" so I assume "several" means 3 or more. The two entries in Table 3 in PMID 29212898 (pediatric LVNC cohort) suggests that this variant segregated with disease in the proband and at least 2 affected family members who underwent known mutation testing, but we have to assume that this family is the same one reported by the GeneDx ClinVar entry. If we conservatively assume that the PMID 29212898 cases were a parent and 2 of their children, this is only 2 meioses. If we get the segregation data from GeneDx proving 3 or more meioses, application of PP1 would upgrade this variant to Likely Pathogenic. MAK - Per Dani, the variant segregated with LVNC in 6 affected individuals from 2 families ("In one family it segregated in 2 individuals and in 4 individuals in another family. In both families it was in association with LVNC."). Not counting data from Miller as being related or definitively from 1 family.
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Residue p.184 is in the defined PM1 region amino acids 181-937. location in this region cannot be used to support pathogenicity for other phenotypes (DCM, LVNC, etc.)
PM6
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
PM3
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Variant found in at least 1 LVNC (Miller et al); 1 HCM + LVNC (Ambry); 2 LVNC, 1 SCD, and 1 HCM with other MYH7 path (GeneDx); 1 LVNC (Invitae) Miller et al. Circ Cardiovasc Genet. 2017 Dec;10(6):e001735. PMID: 29212898 • One hundred twenty-eight individuals diagnosed with LVNC at ≤21 years of age were identified, including 59% with idiopathic pathogenesis, 32% with familial disease, and 9% with a syndromic or metabolic diagnosis. Overall, 75 individuals had either cardiomyopathy gene panel (n=65) or known variant testing (n=10). The yield of cardiomyopathy gene panel testing was 9%. • Table 3 o Lys184Gln reported twice in the table in Isolated LVNC (familial), gene testing for the case was “CM known variant” as opposed to panel, suggesting that this variant was detected in another affected family member first, before testing two pediatric cases. They do not indicate whether these individuals are related in the Table but I would assume they are. o Per text “The specific genetic variants identified in the 13 patients with positive gene panel and known variant testing are summarized in Table 3. Of note, 3 individuals with iLVNC had positive known variant testing, all of whom had a family history of cardiomyopathy.” Abstract from AHA meeting also found via Google Scholar - Very limited details
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