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.3134G>T (p.Arg1045Leu)

CA013375

42948 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 40ccb7f9-d0a7-4e61-9756-8fef5c463031
Approved on: 2021-08-25
Published on: 2021-10-01

HGVS expressions

NM_000257.4:c.3134G>T
NM_000257.4(MYH7):c.3134G>T (p.Arg1045Leu)
ENST00000355349.4:c.3134G>T
ENST00000355349.3:c.3134G>T
NM_000257.3:c.3134G>T
NC_000014.9:g.23422291C>A
CM000676.2:g.23422291C>A
NC_000014.8:g.23891500C>A
CM000676.1:g.23891500C>A
NC_000014.7:g.22961340C>A
NG_007884.1:g.18371G>T
More

Likely Pathogenic

Met criteria codes 4
PP3 PM2 PP1_Moderate PS4_Moderate
Not Met criteria codes 20
PP4 PM6 PM1 PM4 PM5 PM3 PVS1 BA1 BS2 BS4 BS3 BS1 BP3 BP2 BP5 BP7 BP4 PS3 PS2 PS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The c.3134G>T (p.Arg1045Leu) variant in MYH7 has been reported in at least 15 individuals with HCM (PS4_Moderate; Cann 2017 PMID:27000522; Sheikh 2018 PMID:29764897, Walsh 2017 PMID:27532257; GeneDx pers. comm., Invitae pers. comm., LMM pers. comm., OMGL pers. comm.), 4 of whom also had additional variants in other HCM-associated genes (GeneDx pers. comm., Invitae pers. comm., LMM pers. comm.). Because of the additional variants observed in multiple cases, PS4 was downgraded to Moderate. This variant also segregated with HCM in 6 affected relatives from 3 families (PP1_Moderate; Cann 2017 PMID:27000522; GeneDx pers. comm., LMM pers. comm., OMGL pers. comm.). This variant has also been identified in 0.001% (FAF 95% CI, 4/113744) of European chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). 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; PP3.
Met criteria codes
PP3
In silico analysis programs (SIFT, PolyPhen-2, Mutation Taster) predict this variant to have an impact on the protein function
PM2
Popmax FAF in gnomAD is < 0.004%
PP1_Moderate
Total number of segregations: 5 (internal data log)
PS4_Moderate
Total number of probands: 13 (11 from internal data log + 2 from PMID 27000522, 29764897)
Not Met criteria codes
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
not in head domain 181-937 aa
PM4
variant is missense
PM5
A different missense substitution at this codon (p.Arg1045Cys) has been previously reported by our laboratory and other laboratories in ClinVar as likely pathogenic. approved by expert panel
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
variant is missense
BA1
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
BS4
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
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
variant is missense
BP2
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
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
In silico analysis programs (SIFT, PolyPhen-2, Mutation Taster) predict this variant to have an impact on the protein function
PS3
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
PS1
n/a
Curation History
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