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]
  • See Evidence submitted by expert panel for details.

Variant: NM_000257.4(MYH7):c.4283T>C (p.Leu1428Ser)

CA014765

164289 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 94c9fd20-9daa-4b51-920e-f9f8e5ca5632
Approved on: 2021-03-22
Published on: 2021-08-25

HGVS expressions

NM_000257.4:c.4283T>C
NM_000257.4(MYH7):c.4283T>C (p.Leu1428Ser)
ENST00000355349.4:c.4283T>C
ENST00000355349.3:c.4283T>C
NM_000257.3:c.4283T>C
NR_126491.1:n.854A>G
NC_000014.9:g.23417573A>G
CM000676.2:g.23417573A>G
NC_000014.8:g.23886782A>G
CM000676.1:g.23886782A>G
NC_000014.7:g.22956622A>G
NG_007884.1:g.23089T>C
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Uncertain Significance

Met criteria codes 1
PP3
Not Met criteria codes 23
BS4 BS3 BS1 BS2 BP2 BP5 BP7 BP4 BP3 PS1 PS2 PS4 PS3 BA1 PVS1 PP4 PP1 PM5 PM6 PM1 PM4 PM2 PM3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The c.4283T>C (p.Leu1428Ser) variant in MYH7 has been reported in at least 2 individuals with HCM (Alfares 2015 PMID:25611685; Murphy 2016 PMID:26914223; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; LMM per. comm.), but has also been identified in 0.0053% (FAF 95% CI, 12/129150) of non-Finnish European chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, PS4 criterion was not applied (Kelly 2018 PMID:29300372). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to a lack of evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PP3
Met criteria codes
PP3
SIFT and PolyPhen2 are damaging
Not Met criteria codes
BS4
No pedigrees identified.
BS3
data not available
BS1
gnomAD: 0.0093% (12/129159) non-Finnish European chromosomes - FAF = 0.005378% FAF<0.02%
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
no evidence
BP5
no evidence
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
SIFT and PolyPhen2 are damaging
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
none
PS2
No evidence
PS4
2 or 3 individuals in the literature with HCM (unclear if 1 individual had HCM or was a "mutation carrier with no left ventricular hypertrophy"). 1 individual from Amby with HCM. Evidence not applied because PM2 is not met.
PS3
data not available
BA1
gnomAD: 0.0093% (12/129159) non-Finnish European chromosomes - FAF = 0.005378% FAF<0.1%
PVS1
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
PP1
No pedigrees identified.
PM5
none
PM6
No evidence
PM1
outside of head domain (residues 181-937)
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
gnomAD: 0.0093% (12/129159) non-Finnish European chromosomes - FAF = 0.005378% FAF>0.004%
PM3
no evidence
Curation History
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