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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Variant: NM_000257.3(MYH7):c.2539A>G (p.Lys847Glu)

CA012578

177757 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 5dd3f0f6-7736-4320-bd76-d07ae2cd679c
Approved on: 2021-11-30
Published on: 2021-12-09

HGVS expressions

NM_000257.3:c.2539A>G
NM_000257.3(MYH7):c.2539A>G (p.Lys847Glu)
NC_000014.9:g.23424909T>C
CM000676.2:g.23424909T>C
NC_000014.8:g.23894118T>C
CM000676.1:g.23894118T>C
NC_000014.7:g.22963958T>C
NG_007884.1:g.15753A>G
ENST00000355349.4:c.2539A>G
ENST00000355349.3:c.2539A>G
NM_000257.4:c.2539A>G
NM_000257.4(MYH7):c.2539A>G (p.Lys847Glu)
More

Pathogenic

Met criteria codes 4
PP1_Strong PS4 PM1 PM2
Not Met criteria codes 12
BS1 BP2 BP5 BP4 PS1 PS2 PS3 PP3 PM5 PM6 PM3 BA1

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.2539A>G (p.Lys847Glu) variant has been identified in >50 individuals with HCM (PS4; Atiga 2000 PMID:10725281; Kaski 2009 PMID:20031618; Aletras 2011 PMID:21576279; Leung 2013 PMID:23271734; Nunez 2013 PMID:23782526; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ross 2017 PMID:28615295; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute pers. comm.). This variant segregated with disease in 7 affected individuals with HCM in 5 families (PP1_Strong; Ross 2017 PMID:28615295; Invitae pers. comm.; OMGL pers. comm.). 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 (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide evidence for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PP1_Strong, PM2, PM1.
Met criteria codes
PP1_Strong
This variant segregated with disease in 6 affected individuals with HCM in 4 families (PP1_Moderate; Invitae pers. comm.; OMGL pers. comm.) as well as in 1 "affected relative" of a proband with HCM, though specifics were not provided (Ross 2017 PMID:28615295).
PS4
This variant has been identified in >50 individuals with HCM (PS4; Atiga 2000 PMID:10725281; Kaski 2009 PMID:20031618; Aletras 2011 PMID:21576279; Leung 2013 PMID:23271734; Nunez 2013 PMID:23782526; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ross 2017 PMID:28615295; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute pers. comm.). Literature search complete: ClinVar, HGMD, Google INTERNAL DATA: Ambry 3 HCM CHEO 7 HCM GeneDx 13 HCM; Of the 13 HCM probands, only 8 have clinical data provided supporting the HCM diagnosis; of those 2 have VUS on other genes (one has DTNA VUS and the other has MYH6 and TPM! VUS) Invitae 11 HCM, 2 Segregations with HCM in 1 family; 1 HCM proband also has MYL2 VUS p.Asn47Lys and MYH6 VUS p.Arg1361His, 1 HCM proband with MYH6 VUS p.Arg1361His, 1HCM proband with MYH6 VUS p.Arg1361His, 1 HCM proband also has SLC22A5 VUS p.Gly12Ser, 1 HCM proband with TTN VUS p.Val35307Ala, 1 HCM proband with ALPK3 VUS p.Gly1303Asp LMM 1 HCM (+4 HCM in Walsh paper); 1 early onset HCM proband with LV dilation has VUS's in MYH6 (p.Arg1361His) and TTN (p.Cys15965Tyr); 1 HCM proband has another TTN splice varaint (c.38191+1G>A, classified LP by our lab in 2014) and other TTN VUS missense variant (p.Ser30419Leu) OMGL 3 HCM (+10 HCM in Walsh paper), 4 segregations with HCM in 3 families, 1 DCM/RCM Sydney 1 HCM
PM1
Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated
PM2
Absent from gnomAD v2.1.1 with good coverage
Not Met criteria codes
BS1
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
Some cases have been reported in the internal data log with other variants, however these have all been VUS, so not definitive alternate molecular basis for disease.
BP4
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
PS3
Two publications report experimental evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect (Leung 2013 PMID PMID:23271734, Marston 2013 PMID:23712688).
PP3
Tools predict damaging or borderline. REVEL is right at cutoff threshold.
PM5
Note: A single nucleotide deletion at this position which results in an in-frame deletion of this AA has been shown to be LP/P, however this criteria only applies to missense changes.
PM6
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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