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.715G>A (p.Asp239Asn)

CA016679

43100 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8c8707d1-9b0c-4e28-94c8-cc7321eb8840

HGVS expressions

NM_000257.4:c.715G>A
NM_000257.4(MYH7):c.715G>A (p.Asp239Asn)
NC_000014.9:g.23431602C>T
CM000676.2:g.23431602C>T
NC_000014.8:g.23900811C>T
CM000676.1:g.23900811C>T
NC_000014.7:g.22970651C>T
NG_007884.1:g.9060G>A
ENST00000355349.4:c.715G>A
ENST00000355349.3:c.715G>A
NM_000257.3:c.715G>A

Likely Pathogenic

Met criteria codes 4
PM1 PM2 PP1_Moderate PS4_Moderate
Not Met criteria codes 11
PS3 PM6 PM5 PS2 PS1 BA1 BP4 BS4 BS3 BS1 PP3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The c.715G>A (p.Asp239Asn) variant in MYH7 has been identified in at least 13 individuals with HCM (PS4_Moderate; Iascone 2007 PMID:17438619; Kaski 2009 PMID:20031618; Garcia-Pavia 2011 PMID:21896538; Murphy 2016 PMID:26914223; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ingles 2017 PMID:28408708) and segregated with HCM in 5 affected individuals from 4 families (PP1_Moderate; Iascone 2007 PMID:17438619; Garcia-Pavia 2011 PMID:21896538; LMM ClinVar SCV000059647.6 and pers comm). This variant has been identified in 0.003% (1/34592) of Latino chromosomes but is absent from all other populations in gnomAD v2.1.1 (PM2; 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 disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. 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; PM1
Met criteria codes
PM1
The variant is located in a mutational hot-spot, in the the head domain (amino acids 181-937).
PM2
This variant has been identified in 0.003% (1/34592) of Latino chromosomes in gnomAD v2.1.1 (http://gnomad.broadinstitute.org).
PP1_Moderate
This variant segregated with disease in 5 affected individuals with HCM in 4 families (PP1_Moderate; Iascone 2007 PMID:17438619; Garcia-Pavia 2011 PMID:21896538; LMM ClinVar SCV000059647.6 and pers comm). 2 segregations with HCM from 1 family from Garcia-Pavia 2011 PMID:21896538 1 segregation from Iascone 2007 (PMID:17438619) 2 segregations with HCM in 2 families from LMM internal
PS4_Moderate
The c.715G>A (p.Asp239Asn) variant in MYH7 has been identified in at least 13 individuals with HCM (PS4_Moderate; Iascone 2007 PMID:17438619; Kaski 2009 PMID:20031618; Garcia-Pavia 2011 PMID:21896538; Murphy 2016 PMID:26914223; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ingles 2017 PMID:28408708). Iascone 2007 (PMID:17438619) described in ClinVar evidence blurbs, but is only a mutation report: "Aminoacid charge change—aminoacid conserved during evolution—not found in 100 alleles (healthy blood donors)—found in one patient [with HCM]: age at onset 5 years, myectomy at 7 years; the mother is affected and she carried the same mutation. He has another novel mutation in MYBPC3." LMM Internal (overlap with Walsh paper and potentially SHaRe - Homburger paper): Seen it in 5 probands with HCM (14 yrs F; 50 yrs M; 45 yrs F; 26 yrs M; 45 yrs M) Variant segregated with HCM in two affected relatives from 2 families (19yrs M, 24 yrs F). No other variants identified.
Not Met criteria codes
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No de novo evidence
PM5
NM_000257.4(MYH7):c.717C>G (p.Asp239Glu): Listed in ClinVar as VUS with no assertion criteria HGMD has entry with single article (PMID:27247418) - Single case in SHaRe registry, so likely HCM
PS2
No de novo evidence
PS1
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
BP4
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
PP3
Tools are mixed, include REVEL, SIFT (per Alamut is Tolerated with score of 0.44), and others below.
Approved on: 2021-03-22
Published on: 2021-08-25
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