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.1148A>G (p.Lys383Arg)

CA010281

42826 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 2ca8bdd3-0ce4-4b88-a814-cd56ca1a4dac
Approved on: 2021-03-22
Published on: 2021-08-25

HGVS expressions

NM_000257.4:c.1148A>G
NM_000257.4(MYH7):c.1148A>G (p.Lys383Arg)
NC_000014.9:g.23429338T>C
CM000676.2:g.23429338T>C
NC_000014.8:g.23898547T>C
CM000676.1:g.23898547T>C
NC_000014.7:g.22968387T>C
NG_007884.1:g.11324A>G
ENST00000355349.4:c.1148A>G
ENST00000355349.3:c.1148A>G
NM_000257.3:c.1148A>G
More

Uncertain Significance

Met criteria codes 2
PM1 PM2
Not Met criteria codes 23
PM4 PM6 PM5 PM3 BA1 PVS1 BS4 BS3 BS1 BS2 BP2 BP5 BP4 BP3 BP1 PS4 PS2 PS1 PS3 PP1 PP3 PP4 PP2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The c.1148A>G (p.Lys383Arg) variant in MYH7 has been reported in at least 1 individual with HCM (Gruner 2011 PMID: 21511876; Walsh 2017 PMID:27532257); however due to potential overlap in the individuals reported, PS4_Supporting criteria is not met. This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v.2.1.1). 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 disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficience 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; PM1
Met criteria codes
PM1
Variant present in designated PM1 domain (AA 181-937)
PM2
Variant not present in gnomAD, good coverage ~90X
Not Met criteria codes
PM4
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
PM5
There is also Lys>Asn reported as a de novo mutation in an HCM patient (Kuang et al, PMID 8899546) which reaches likely pathogenic (PS2, PM1, PM2, PP3). PM5 evaluated but not applied because K383N is likely pathogenic but not pathogenic
PM3
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
PVS1
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
BS2
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
BP5
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
BP3
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
PS4
Appears to be 2 HCM cases in literature (PMIDs 27532257; 21511876) but Gruner et al. indicates patients in their Toronto cohort underwent a “commercially available test” so unclear if they may have been tested via Harvard LMM, which is where the other case was reported from in Walsh et al. No apparent author overlap) This variant has been reported in at least 1 individual with HCM (Gruner 2011 PMID: 21511876; Walsh 2017 PMID:27532257); however due to potential overlap in the individuals reported, PS4_Supporting criteria is not met.
PS2
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
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
Align GVGD: C0 SIFT: Tolerated --> MAK: SIFT is DAMAGING below, but TOLERATED via ALAMUT. MutationTaster: disease causing PolyPhen-2= Probably damaging REVEL 0.806 is >0.75 cut off for pathogenic. Lys>Arg is a small amino acid change, Grantham distance = 26. Highly conserved (91/91 species in UCSC, but 10/12 species in Alamut and the residue is an Arginine in fruitfly and C elegans.) Overall, somewhat mixed for PP3, but the high conservation in UCSC would suggest potential for impact of a substitution at this residue. There is also Lys>Asn reported as a de novo mutation in an HCM patient (Kuang et al, PMID 8899546) which reaches likely pathogenic (PS2, PM1, PM2, PP3) but PM5 cannot be applied for Lys383Arg because Lys383Asn is only likely pathogenic. Taken together, this evidence along with the conservation seems reasonable to apply PP3. MAK: I would consider this evidence mixed enough to NOT apply.
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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