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_000257.4(MYH7):c.1273G>A (p.Gly425Arg)

CA010465

42834 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 999e2490-4ce6-429e-9266-c2865c0336df

HGVS expressions

NM_000257.4:c.1273G>A
NM_000257.4(MYH7):c.1273G>A (p.Gly425Arg)
NC_000014.9:g.23429089C>T
CM000676.2:g.23429089C>T
NC_000014.8:g.23898298C>T
CM000676.1:g.23898298C>T
NC_000014.7:g.22968138C>T
NG_007884.1:g.11573G>A
ENST00000355349.4:c.1273G>A
ENST00000355349.3:c.1273G>A
NM_000257.3:c.1273G>A

Uncertain Significance

Met criteria codes 4
PM2_Supporting PM1 PP3 PS4_Supporting
Not Met criteria codes 22
BS2 BS4 BS3 BS1 BP3 BP1 BP7 BP4 BP5 BP2 PS3 PM4 PM3 PM6 PM5 PS2 PS1 PP1 BA1 PP2 PP4 PVS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The c.1273G>A (p.Gly425Arg) variant in MYH7 has been identified in at least 3 individuals with HCM, the majority of whom are of Chinese ancestry (PS4_Supporting; Song 2005 PMID:15563892; Wang 2009 PMID:19586842; Homburger 2016 PMID:27247418; Mak 2018 PMID:29497013). This variant segregated with disease in 2 relatives with HCM from 1 family (Wang 2009 PMID:19586842); however this data is currently insufficient to apply PP1. This variant was absent from large population studies (PM2_Supporting; http://gnomad.broadinstitute.org, v2.1.1). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. 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 suggest that this variant may impact the protein (PP3). In summary, due to insufficient 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): PS4_Supporting; PM2_Supporting; PM1; PP3.
Met criteria codes
PM2_Supporting
Absent from gnomAD with >30x coverage in genomes and ~100x coverage in exomes
PM1
Variant is located within the MYH7 head domain
PP3
10 in silico scores from Varsome all in agreement of a deleterious role (basically same tools as listed below).
PS4_Supporting
This variant has been identified in at least 3 individuals with HCM, the majority of whom are of Chinese ancestry (PS4_Supporting; Song 2005 PMID:15563892; Wang 2009 PMID:19586842; Homburger 2016 PMID:27247418; Mak 2018 PMID:29497013). Uncertain of source for internal data: Needs verification since not listed in ClinVar, not including in counts (wouldn't impact classification) 1 x LMM case with HCM 1 x GeneDx case with HCM, father affected but no GT 1 x Sydney case with Brugada/unexplained VF arrest and no evidence of LV
Not Met criteria codes
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 data
BS1
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
BP7
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
BP5
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
PS3
No data
PM4
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
PM6
No data
PM5
NM_000257.4(MYH7):c.1274G>C (p.Gly425Ala): Listed in ClinVar as novel VUS No variants listed in HGMD at this codon other than the one being evaluated.
PS2
No data
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
Wang 2009 PMID:19586842 - Abstract only since article is in Chinese: Chinese family with HCM; Variant listed in abstract as found in 4 family members. Per ClinVar entry from Stanford, who had someone able to read the article, "the variant was seen in three family members with HCM and one obligate carrier". Likely the same family as reported by Song et al. 2005. Unable to confirm segregations with original article so not counting. Article reviewed by Emily Qian and was able to verify details: II-2 proband is 42 yrs F, presented at 36 yrs with shortness of breath (SOB) and chest pain, had abnormal EKG w/ left BBB and echo showed 13 mm LVH and SAM. I-2 proband’s mom is 67 yrs F, presented at 50 yrs with SOB, history of syncope, and chest pain. abnormal EKG and echo showed 23 mm LVH. III-2, proband’s nephew is 10 yrs M, presenting with SOB and chest pain after sports. abnormal EKG and echo showed 13 mm LVH and SAM. II-3 is an asymptomatic carrier [proband's sister]. normal EKG and echo
BA1
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
PP4
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
Approved on: 2022-07-30
Published on: 2022-07-30
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