MYH7c.2548G>AUncertain significance

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Variant interpretation report

MYH7 c.2548G>A, p.(Ala850Thr)

NM_000257.3:c.2548G>A NP_000248.2:p.(Ala850Thr) View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About MYH7

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 moderate (pathogenic) · 2 supporting (pathogenic)
Expert rules: ClinGen MYH7 VCEP v2.0
Other laboratories (ClinVar): 4 Uncertain significance · 1 Uncertain Significance · 1 Likely pathogenic
Pipeline record: 17 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PM1 (moderate): Codon 850 lies within the VCEP-defined MYH7 missense cluster region (codons 167-931) per Walsh et al. 2019 (PMID:30696458). This region shows significant enrichment of rare missense variants in HCM case cohorts.
PM2 (supporting): Variant is extremely rare in population databases. gnomAD v2.1 NFE AF = 8.79e-6 (1/113,748 alleles), well below the VCEP PM2 threshold of ≤0.00004. Absent from Ashkenazi Jewish and Other subpopulations. gnomAD v4.1 grpmax FAF = 7.9e-7.
PP3 (supporting): REVEL score 0.809 exceeds the VCEP-recommended threshold of ≥0.70 for PP3 application. SpliceAI predicts no splice impact (max delta = 0.00), so the in silico signal is confined to missense pathogenicity prediction.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is ClinGen MYH7 VCEP v2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PM1Moderate

PM1 · moderate

Codon 850 lies within the VCEP-defined MYH7 missense cluster region (codons 167-931) per Walsh et al. 2019 (PMID:30696458). This region shows significant enrichment of rare missense variants in HCM case cohorts.

PM2Supporting

PM2 · supporting

Variant is extremely rare in population databases. gnomAD v2.1 NFE AF = 8.79e-6 (1/113,748 alleles), well below the VCEP PM2 threshold of ≤0.00004. Absent from Ashkenazi Jewish and Other subpopulations. gnomAD v4.1 grpmax FAF = 7.9e-7.

PP3Supporting

PP3 · supporting

REVEL score 0.809 exceeds the VCEP-recommended threshold of ≥0.70 for PP3 application. SpliceAI predicts no splice impact (max delta = 0.00), so the in silico signal is confined to missense pathogenicity prediction.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYH7 Version 2.0 v2.0 criteria-combination framework was evaluated deterministically with applied criteria: PM1 moderate, PM2 supporting, PP3 supporting; no rule matched the adjudicated criteria.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

4 / 1,614,204 alleles

gnomAD v4.1: 4 / 1,614,204 alleles. Recorded AF 2.478e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.97662e-06; MAF= 0.00040%, 1/251470 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79136e-06; MAF= 0.00088%, 1/113748 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

6 reported laboratory submissions

4 Uncertain significance · 1 Uncertain Significance · 1 Likely pathogenic. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗

No screenshot for this evidence

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen MYH7 VCEP v2.0, with the data and sources behind each one.

26 criteria with recorded statuses: 3 met · 13 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000257.3:c.2548G>A (p.Ala850Thr) is a missense variant in MYH7 exon 22. It is extremely rare in population databases (gnomAD v2.1 AF 3.98e-6, v4.1 grpmax FAF 7.9e-7), satisfying VCEP PM2 at supporting strength.

Codon 850 falls within the VCEP-defined MYH7 missense cluster region (codons 167-931), meeting PM1 at moderate strength per Walsh et al. 2019 (PMID:30696458).

REVEL in silico meta-predictor score is 0.809, exceeding the VCEP PP3 threshold of ≥0.70, providing supporting evidence for a deleterious effect. SpliceAI predicts no splice impact.

A sister missense variant at the same codon, p.Ala850Asp, was reported as a novel mutation in one HCM patient by Fokstuen et al. 2008 (PMID:18409188), but lacks formal VCEP classification necessary for PM5 application.

No functional studies, segregation data, de novo observations, or case-control data were identified for this specific variant in any reviewed publication.

The variant has been reported in ClinVar (ID 403207) as Uncertain Significance by 5 clinical laboratories and Likely Pathogenic by 1 (Invitae). No expert panel classification has been assigned. ClinVar review status is 'criteria provided, single submitter' at the aggregate level.

Applying the MYH7 VCEP v2.0 classification rules: 1 moderate criterion (PM1) and 2 supporting criteria (PM2_Supporting, PP3) are met. This combination does not satisfy any VCEP Likely Pathogenic rule (minimum: Rule 14 requires 2 moderate + ≥2 supporting; Rule 15 requires 1 moderate + ≥4 supporting). The variant remains a Variant of Uncertain Significance.

Met · 3

PM1 ModerateCodon 850 lies within the VCEP-defined MYH7 missense cluster region (codons 167-931) per Walsh et al. 2019 (PMID:30696458). This region shows significant enrichment of rare missense variants in HCM case cohorts. Details ▾Hide ▴

Evidence considered

VCEP MYH7 v2.0 PM1 specification: codons 167-931 eligible
Codon 850 falls within the defined cluster region.

Sources

cspec ↗

PM2 SupportingVariant is extremely rare in population databases. gnomAD v2.1 NFE AF = 8.79e-6 (1/113,748 alleles), well below the VCEP PM2 threshold of ≤0.00004. Absent from Ashkenazi Jewish and Other subpopulations. gnomAD v4.1 grpmax FAF = 7.9e-7. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: 1/251
470 total alleles (AF 3.98e-6)
gnomAD v2.1 NFE: 1/113
748 (AF 8.79e-6)
absent from ASJ/OTH
gnomAD v4.1: 4/1
614
204 alleles
grpmax FAF = 7.9e-7

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

PP3 SupportingREVEL score 0.809 exceeds the VCEP-recommended threshold of ≥0.70 for PP3 application. SpliceAI predicts no splice impact (max delta = 0.00), so the in silico signal is confined to missense pathogenicity prediction. Details ▾Hide ▴

Evidence considered

REVEL score: 0.809 (≥0.70 threshold met)
SpliceAI max delta: 0.00 (no splice impact)

Still missing

BayesDel score 0.246 is discordant but REVEL is the VCEP-preferred meta-predictor.

Sources

revelspliceai ↗cspec ↗

Not met · 13 · evaluated, threshold not reached

PS1 No evidence of a different nucleotide change at codon 850 producing the same amino acid change (p.Ala850Thr). Details ▾Hide ▴

Still missing

No nucleotide-level comparator producing p.Ala850Thr identified in ClinVar or literature.

PS2 No de novo observation reported for NM_000257.3:c.2548G>A in any reviewed publication or ClinVar submission. Details ▾Hide ▴

Still missing

No de novo data available.

PS3 No variant-specific functional experimental data identified for c.2548G>A (p.Ala850Thr) in any reviewed publication. Reviewed papers are cohort studies, methods papers, or consensus guidelines without MYH7-specific functional assays. Details ▾Hide ▴

Still missing

No functional studies (in vitro or in vivo) testing p.Ala850Thr or systematically characterizing codon 850.

PS4 No case-control data available with variant-specific counts for c.2548G>A. Cohort studies reviewed (Walsh et al. 2017, Mazzarotto et al. 2019, Oktay et al. 2023) do not report individual variant frequencies usable for PS4 calculation. Details ▾Hide ▴

Evidence considered

Variant absent from Walsh et al. 2017 and Mazzarotto et al. 2019 case-level reporting.

Still missing

No case-control odds ratio or allele count comparison available for this variant.

PM5 A different missense variant at the same codon (p.Ala850Asp) is reported as a novel mutation in PMID:18409188, absent in 192 controls. However, p.Ala850Asp has not been formally classified as pathogenic or likely pathogenic under VCEP guidelines, so the VCEP PM5 requirement for a classified comparator is not satisfied. Details ▾Hide ▴

Evidence considered

p.Ala850Asp reported in one HCM patient
absent in 192 control chromosomes
conserved residue (Fokstuen et al. 2008). No formal VCEP classification available.

Still missing

p.Ala850Asp requires formal VCEP classification before PM5 can be applied at any strength.

Sources

PMID:18409188 ↗

PM6 No assumed or confirmed de novo observation for c.2548G>A identified in any reviewed publication. Details ▾Hide ▴

Still missing

No de novo data available.

PP1 No segregation data available for this variant in any reviewed publication. Details ▾Hide ▴

Still missing

No family segregation analysis reported.

BA1 gnomAD v4.1 grpmax FAF = 7.9e-7, far below the VCEP BA1 threshold of ≥0.001. Variant is extremely rare in all populations. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF: 7.9e-7 (threshold: ≥0.001)

Sources

gnomad_v4 ↗cspec ↗

BS1 gnomAD v4.1 grpmax FAF = 7.9e-7, far below the VCEP BS1 threshold of ≥0.0001 for MYH7. No subpopulation approaches the threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF: 7.9e-7 (threshold: ≥0.0001)

Sources

gnomad_v4 ↗cspec ↗

BS3 No functional studies demonstrating a benign effect for c.2548G>A (p.Ala850Thr) identified in any reviewed publication. Details ▾Hide ▴

Still missing

No functional data supporting benign impact.

BS4 No non-segregation data reported for this variant. VCEP requires ≥2 non-segregations unlikely to be phenocopies. Details ▾Hide ▴

Still missing

No family segregation or non-segregation data available.

BP2 No evidence of this variant observed in cis or trans with a pathogenic variant in MYH7 or another cardiomyopathy gene. Details ▾Hide ▴

Still missing

No phase data with other pathogenic variants.

BP4 REVEL score 0.809 is well above the VCEP BP4 threshold of ≤0.40. In silico predictions support a deleterious effect, not a benign one. Details ▾Hide ▴

Evidence considered

REVEL score: 0.809 (BP4 threshold: ≤0.40)

Sources

revelcspec ↗

Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 VCEPMYH7 VCEP specifies PVS1 as not applicable; this is a missense variant (c.2548G>A, p.Ala850Thr), not a null variant. Details ▾Hide ▴

No further detail was recorded.

PP2 VCEPVCEP MYH7: not applicable; regional missense enrichment is captured by PM1 instead of PP2 per the specification (Walsh et al. 2019 PMID:30696458). Details ▾Hide ▴

Sources

cspec ↗

PP4 VCEPVCEP MYH7: not applicable; inherited cardiomyopathies have high locus heterogeneity and non-genetic etiologies, precluding phenotype specificity for a single genetic etiology. Details ▾Hide ▴

Sources

cspec ↗

PP5 VCEPVCEP MYH7: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴

Sources

cspec ↗

BS2 VCEPVCEP MYH7: not applicable; inherited cardiomyopathies display reduced penetrance, variable expressivity, and adult-onset, so observation in a healthy adult does not constitute strong benign evidence. Details ▾Hide ▴

Sources

cspec ↗

BP1 VCEPVCEP MYH7: not applicable; for genes where null variants are a known disease mechanism, pathogenic missense variants have also been reported. Missense variants in MYH7 are an established cause of cardiomyopathy. Details ▾Hide ▴

Sources

cspec ↗

BP5 VCEPVCEP MYH7: not applicable; co-occurrence with a pathogenic variant for a non-cardiomyopathy disease does not reduce likelihood of independent pathogenicity for cardiomyopathy. Details ▾Hide ▴

Sources

cspec ↗

BP6 VCEPVCEP MYH7: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴

Sources

cspec ↗

BP7 N/AVCEP BP7 applies to synonymous variants and intronic variants outside the splice consensus; this is a missense variant (c.2548G>A, p.Ala850Thr). Details ▾Hide ▴

Sources

cspec ↗

PS5 N/ANo alternative nucleotide change at the same codon producing the same amino acid (p.Ala850Thr) is known. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: MYH7
Transcript: NM_000257.3
Coding (HGVS c.): NM_000257.3:c.2548G>A
Protein (HGVS p.): NP_000248.2:p.(Ala850Thr)
GRCh38: chr14:23424900 C>T
GRCh37: chr14:23894109 C>T
ClinVar: 403207

Gene diagram

Every interpreted variant in MYH7, mapped onto the exon structure of NM_000257.3. Select a row to find it on the plot.

MYH7NM_000257.3

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in MYH7 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 4 / 1,614,204 alleles AF 2.48e-06 · 0 homozygotes · FAF 7.9e-07

gnomAD v2.1 1 / 251,470 alleles AF 3.98e-06 · 0 homozygotes

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 2.5e-06 · 4 / 1,614,204 alleles · 0 hom · FAF 7.9e-07

European (non-Finnish)4 / 1,180,046

3.4e-06

0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 4e-06 · 1 / 251,470 alleles · 0 hom

European (non-Finnish)1 / 113,748

8.8e-06

0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.478e-06; MAF= 0.00025%, 4/1614204 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.3897e-06; MAF= 0.00034%, 4/1180046 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +102 bp

0.000

SpliceAI acceptor gainat +42 bp

0.000

SpliceAI donor lossat +386 bp

0.000

SpliceAI donor gainat -128 bp

0.000

Pangolin splice lossmagnitude shown

-0.010

Pangolin splice gain

0.000

Other predictors

REVEL: 0.809
BayesDel: 0.246

How the predictions were used

Evidence considered

REVEL score: 0.809 (≥0.70 threshold met)
SpliceAI max delta: 0.00 (no splice impact)

Still missing

BayesDel score 0.246 is discordant but REVEL is the VCEP-preferred meta-predictor.

Sources

revelspliceai ↗cspec ↗

BP4 REVEL score 0.809 is well above the VCEP BP4 threshold of ≤0.40. In silico predictions support a deleterious effect, not a benign one. Details ▾Hide ▴

Evidence considered

REVEL score: 0.809 (BP4 threshold: ≤0.40)

Sources

revelcspec ↗

BP7 N/AVCEP BP7 applies to synonymous variants and intronic variants outside the splice consensus; this is a missense variant (c.2548G>A, p.Ala850Thr). Details ▾Hide ▴

Sources

cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.809. BayesDel score = 0.246045.

9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy.

Fokstuen S et al. · 2008

Reports p.Ala850Asp (c.2549C>A), a different missense change at the same codon, as a novel mutation in one HCM patient. Variant was absent in 192 Caucasian control chromosomes and affects a conserved residue. The patient (DE2, male, diagnosed at age 32) presented with moderate hypertrophy and latent LVOT gradient, receiving an ICD for inducible ventricular tachycardia. NM_000257.3:c.2548G>A (p.Ala850Thr) was not identified in this paper.
Does not name this variant
PMID 18409188 ↗
Quoted passage
Patient DE2 with a novel missense mutation in exon 22 (p.Ala850Asp) of MYH7 presented with moderate hypertrophy and latent left ventricular outflow tract (LVOT) gradient but received an implantable cardioverter defibrillator (ICD) because of inducible ventricular tachycardia.
Table 2, Results section; Table 3 (patient DE2 clinical features)
A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H et al. · 2013

Describes a variant assessment tool (VAT) for systematic evaluation of clinical significance of genetic variants. NM_000257.3:c.2548G>A was not identified in this paper.
Does not name this variant
PMID 24033266 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S et al. · 2015

ACMG/AMP standards and guidelines for sequence variant interpretation. NM_000257.3:c.2548G>A was not identified in this paper.
Does not name this variant
PMID 25741868 ↗
Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe).

Ho CY et al. · 2018

SHaRe registry analysis of 4,591 HCM patients examining genotype-phenotype correlations and lifetime disease burden. NM_000257.3:c.2548G>A was not identified in this paper.
Does not name this variant
PMID 30297972 ↗
[The role of mutation in cardiac beta-myosin heavy chain gene in population of patients].

Seleznev DM et al. · 2005

No paper-specific finding is recorded.

PMID 15940186 ↗
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.

Walsh R et al. · 2017

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. NM_000257.3:c.2548G>A was not identified in this paper.
Does not name this variant
PMID 27532257 ↗
Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center.

Mazzarotto F et al. · 2019

Analysis of 19 years of HCM genetic testing results defining diagnostic effectiveness of genes. NM_000257.3:c.2548G>A was not identified in this paper.
Does not name this variant
PMID 29875424 ↗
The Definition of Sarcomeric and Non-Sarcomeric Gene Mutations in Hypertrophic Cardiomyopathy Patients: A Multicenter Diagnostic Study Across Türkiye.

Oktay V et al. · 2023

Multicenter Turkish study of sarcomeric and non-sarcomeric gene mutations in 392 HCM patients. NM_000257.3:c.2548G>A was not identified in this paper.
Does not name this variant
PMID 37466024 ↗
HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA).

Ackerman MJ et al. · 2011

No paper-specific finding is recorded.

PMID 21810866 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 4 / 1,614,204 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar 4 Uncertain significance · 1 Uncertain Significance · 1 Likely pathogenic Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 403207)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.809. BayesDel score = 0.246045.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.