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Please note this is a beta version of the ClinGen Evidence Repository. This resource is intended to provide access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants. In this beta version, the evidence is limited to curation notes and referenced literature (PMIDs).

For general information about ClinGen Expert Panels and Variant Curation please visit: Clinical Domain Working Groups. For specific inquiries regarding a variant classification or evidence curation (e.g. population database queried, segregation counts or other evidence used) or to submit general comments about the evidence repo, please email us.

The resource is undergoing updates and tesing. Should you encounter any issues regarding the data displayed, lack of functionality or other problems, please let us know so we can rectify these accordingly. Your help in this regard is greatly appreciated.

ACMG variant classification (RASopathy)

Benign
Pathogenic
Stand Alone
Strong
Supporting
Supporting
Moderate
Strong
Very Strong
Population Data

Allele frequency is above 5% In Exome Sequencing Project, 1000 Genomes, or ExAC Allele frequency is greater than expected for disorder
* ExAC filtering allele frequency ≥0.0005 (BA1) BA1

Allele frequency is above 5% In Exome Sequencing Project, 1000 Genomes, or ExAC Allele frequency is greater than expected for disorder
* BS1 is sufficient as stand-alone for likely benign classification in the absence of contradictory pathogenic evidence.
* ExAC filtering allele frequency ≥0.00025. Based on disease prevalence of 1:1000 (BS1) BS1

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age
* Due to variable expressivity and severity, population data should not be used for this criteria. Individuals must be well-phenotyped.
* ≥3 well phenotyped individuals. BS2

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
*Due to variable expressivity and severity, individuals must be well-phenotyped.
*1-2 independent occurrences PS4-Supporting

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
* Due to variable expressivity and severity, individuals must be well-phenotyped.
* 3-4 independent occurrences PS4-Moderate

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or ExAC
* The variant must be completely absent from all population databases. PM2

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
* Due to variable expressivity and severity, individuals must be well-phenotyped.
* ≥5 independent occurrences PS4

Computational And Predictive Data

Missense variant in a gene for which primarily truncating variants are known to cause disease
* CONTRAINDICATION: Truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) when only known disease mechanism for gene is gain-of-function. BP1

In-frame deletions/insertions in a repetitive region without a known function
* Follows primary definition of BP3 BP3

Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
* Follows primary definition of BP4 BP4

A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
* Also applicable for intronic or non-coding variants and can be used in conjunction with BP4. BP7

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
* Follows of primary definition of PP3 PP3

Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants. PM4

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
* Previously established variant(s) must be established as pathogenic per these criteria for germline RASopathy variants. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes.
* This rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a 'mutational hot-spot'.
* Can also be applied for the same analogous residue positions/regions in highly analogous groupings:
*
* Group 2: BRAF, RAF1
*
* Group 3: HRAS, KRAS, NRAS
*
* Group 4: MAP2K1, MAP2K2
*
* Group 5: SOS1, SOS2 PM5

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
* Previously established variant(s) must be established as pathogenic per these criteria for germline RASopathy variants. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes.
* This rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a 'mutational hot-spot'.
* ≥2 different pathogenic missense changes PM5-Strong

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
* Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants.
* Can also be applied for the same analogous residue positions/regions in highly analogous groupings:
*
* Group 2: BRAF, RAF1
*
* Group 3: HRAS, KRAS, NRAS
*
* Group 4: MAP2K1, MAP2K2
*
* Group 5: SOS1, SOS2 PS1

Functional Data

Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing
* Follows primary definition of BS3 BS3

Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
* Follows primary of definition of PP2 PP2

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation
* Can also be applied for the same analogous residue positions/regions in highly analogous groupings:
*
* Group 2: BRAF, RAF1
*
* Group 3: HRAS, KRAS, NRAS
*
* Group 4: MAP2K1, MAP2K2
*
* Group 5: SOS1, SOS2 PM1

Well-established in vitro or in vivo functional studies strongly supportive of a damaging effect on gene or gene product. PS3

Segregation Data

Lack of segregation in affected members of a family
* Due to variable expressivity and severity, individuals must be well-phenotyped.
* ≥1 meiosis BS4

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease
* Due to variable expressivity and severity, individuals must be well-phenotyped
* 3-4 meioses PP1

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease
* Due to variable expressivity and severity, individuals must be well-phenotyped
* 5-6 meioses PP1-Moderate

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease
* Due to variable expressivity and severity, individuals must be well-phenotyped
* ≥7 meioses PP1-Strong

De novo Data

Assumed de novo, but without confirmation of paternity and maternity.
* Dual application of both unmodified PS2 and PM6 is only acceptable with a singleton occurrence in each category.
* 1 occurrence without confirmation PM6

Assumed de novo, but without confirmation of paternity and maternity
* Dual application of both unmodified PS2 and PM6 is only acceptable with a singleton occurrence in each category.
* 2-3 independent occurrences of PM6 assumed de novo mutations without confirmation of paternity and maternity. PM6-Strong

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history
* Dual application of both unmodified PS2 and PM6 is only acceptable with a singleton occurrence in each category.
* 1 occurrence with parental confirmation PS2

Assumed de novo, but without confirmation of paternity and maternity ≥ 4 occurrences with or without confirmation PM6-Very Strong

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
* Dual application of both unmodified PS2 and PM6 is only acceptable with a singleton occurrence in each category.
* ≥ 2 occurrences with parental confirmation OR 3 occurrences, at least 1 with parental confirmation PS2-Very Strong

Allelic Data

Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern
* Follows primary definition of BP2 BP2

Other Data

Variant found in a case with an alternate molecular basis for disease
* Follows primary definition of BP5 BP5

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